CN102663248B - The method adopting multi-dimensional matrix reference market that compound structure can be provided to carry out medicine framework compound design and application thereof - Google Patents
The method adopting multi-dimensional matrix reference market that compound structure can be provided to carry out medicine framework compound design and application thereof Download PDFInfo
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Abstract
The present invention relates to the method for designing of multi-dimensional matrix for the application and medicine framework compound structure type that design medicine framework compound structure type, the matrix optimizing theory of mathematics is applied to medicine framework compound structure type and relevant MOLECULE DESIGN thereof by the method first, and adopt the core texture of multi-dimensional matrix arrangement analysis target compound and variable factor and variable thereof, generate the medicine framework compound structure type possessing desired properties, and creatively adopt multi-dimensional matrix and carry out structure analysis in conjunction with empirical data, structural confirmation, structural design and structure optimization, have studied the correlativity between medicine framework structure type and empirical data all sidedly and systematically, significantly improve the specific aim of medicine framework compound structure type design, validity, comprehensive, systematicness, rationality and design efficiency, the intermediate needed for pharmaceutical synthesis or reagent are greatly enriched, significantly shorten the time of medicament research and development, and significantly reduce the R & D Cost of medicine.
Description
Technical field
The invention belongs to medicine framework compound molecule method for designing field, relate to and adopt multi-dimensional matrix to carry out method and the application thereof of medicine framework compound molecule design with reference to the available compound structure type in market.
The special art of background
Over nearly 100 years, medicament research and development experienced by the following stage, and 1) target discovery; 2) target checking; 3) high flux screening (HighThroughputScreening, HTS); 4) Hit-to-Lead; 5) lead compound; 6) clinical researches etc., wherein, target Qualify Phase and SARS drug design are acknowledged as the technical bottleneck of medicament research and development.
Last century Mo and the beginning of this century, genetic engineering and protein engineering achieve rapid progress.Wherein, genetic engineering has found the target proteins matter type that about 12000-15000 kind is novel, but the deviation between the Expected Results of the newtype drug using these modulations to develop and its actual efficacy is very large, causes world's pharmacy and medicament research and development industry meet with huge loss and feel puzzled deeply.At present, the 300-500 be still extensively examined the biological target type that international drugs research and development industry is mainly used, and have multi-medicament screening synthetic method to be applied widely.
High flux screening (HTS) is the drug screening means of widespread use in current medical research and development.The result of research large database shows, the high flux screening classes of compounds for drug development process has 1500-2000 ten thousand.Although high flux screening filters out the compound of more than 120,000 every day by automation equipment, it is subject to again many technical limitation: the 1) accuracy of biological target, needs the biological target that can be used for automation process possessing degree of accuracy under trace; 2) raising of detection means, needs the checkout equipment of high-resolution, as high-quality genetic chip; 3) high-quality compound collection, generally comprise the compound that 300-500 ten thousand kinds is selected, as having the high quality compound of picture Types of Medicine characteristic, the compound etc. that medicament research and development project is relevant, not only need quality and the purity of considering compound, also to consider the chemical space compound amounts that compound structure type can represent, comprise the diversity (Diversity) of compound and the picture property of medicine (DrugLikeness) etc.
The MOLECULE DESIGN of " as medicine " type compound and exploitation are by one of Research Emphasis becoming world's pharmaceutical industry.Possible drug molecule number as Types of Medicine compound is 10
63the main difficulty that the method faces how therefrom effectively to find the compound structure type possessing particular organisms effect? the chemical space of " as medicine " type compounds represented how is made effectively closely to be combined with the biological space representated by albumen target, increase new compound structure species and number? the limitation of its exploitation is, the validity of MOLECULE DESIGN and the diversity of available medicine framework compound (BuildingBlock) kind, and become another technical bottleneck of medicament research and development.
Hit-to-Lead becomes the Main Means of medicament research and development, and is formally introducing medicament research and development industrial chain in recent years.The method is first by high flux screening " as Types of Medicine " compound, to confirm one group of reactive compound (" Hit "), reevaluate and optimize reactive compound to obtain lead compound (" Lead '); and through repeatedly screening and optimizing lead compound structure type, with effectively and accurately in the result of high flux screening optimization be directed to that particular organisms target possesses can the compound structure of druggability.Usually, need to expend 4-6 from the synthesis of compound, screening, pharmacological effect, the structure optimization that completes compound, and need to carry out a large amount of MOLECULE DESIGN and molecular structure contrast work, therefore it is poor to there is systematicness, and the defect such as need to combine with MOLECULE DESIGN theory.
At present, the optimization of guiding compound becomes again the key of medicament research and development, guiding compound after optimizing is carried out MOLECULE DESIGN and molecular structure contrast, to obtain the compound structure of core, then by structural modification to realize following effect: 1) at utmost increase the biologically active for particular target; 2) keeping bioactive to particular target while, its selectivity is increased; 3) function to specific cells and activity is increased; 4) the in vivo studies effect of compound is optimized; 5) characteristic such as absorption, distribution, metabolism, excretion, toxicity (ADME/T) of compound is regulated; 6) coordinate and meet the demand of compound in preparation, administering mode, induction system, bioavilability etc.
But the optimizing process of existing lead compound is more mechanical and loaded down with trivial details, relates to the structural modification of the aspect such as substituting group, heteroatoms composition, molecular shape of adjustment lead compound, make it possess " as medicine " property.Usually, the compound that need have core texture for 1-3 carries out structure of modification, study the relation (SAR) between compound structure and its biologically active again, and the medicine of binding compounds optimizes compound structure for character such as pharmacology toxic and side effects, need the compound of synthesis more than 5000 more, the design efficiency of compound molecule is lower, does not also effectively utilize existing drug research data and drug research means.
" for " property miniaturization compound collection (FocusedLibrary) is also be used for one of method improving drug screening efficiency at present, the method about comprises 500-2,000 compound, carries out the design of compound mainly for specific compound target based on target (TargetOrientated), diversity (DiversityOrientated), natural products (NaturalProductOrientated), compound basic structural unit (FragmentOrientated) etc.But these designs are all based on the single factors that medicine biologically active is relevant, relevance between little Consideration, do not consider to affect with other compound carries out Relative quantification Comprehensive Correlation and assessment as the structure of the property of medicine, more do not make full use of existing empirical data yet.Therefore, the compound molecule design in this collection is tending towards single, has a strong impact on the design efficiency of compound structure.
In broad terms, " as medicine " type compound may become medicine, has strong compatibility and specific selectivity to specific biological target, also has acceptable and absorbs, distribution, metabolism, the character such as eliminating and toxicity (ADME/T).The character of " as medicine " type compound comes from research to known drug and summary mostly, but known drug does not represent kind and the feature of all " as medicine " type compound, the structure species of known drug also only covers a little part (WaltersWP of " as medicine " type compound, StahlMT, andMurckoMA.VirtualScreening:Anoverview.DrugDiscoveryTod ay1998; 3:160-78; WaltersWP, MurckoA, MurckoMA.RecognizingMoleculeswithdrug-likeproperties.Cur rOpinChemBiol1999; 3:384-7).The chemical space that " as medicine " type compound occupies is an astronomical figure.How making the chemical space of compounds represented effectively closely be combined with the biological space representated by albumen target to be the key of drug development, is also the key increasing novel compounds species and number.
Lipinski thinks: " as medicine " type compound should have sufficient, acceptable ADME/T (absorb, distribution, metabolism, get rid of and toxicity) character, and will pass through a clinical trial phase.Lipinski points out " as medicine " type compound is distributed in one extremely widely among chemical space, approximately comprise 1040-10100 " as medicine " type compound, relative to possible biological target, find that the probability of a reactive compound is less than 1/1014.The physical property of " as medicine " compound determines whether compound may become reactive compound (C.A.Lipinski to a great extent; F.Lombardo; B.W.DominyandP.J.Feeney (1997). " Experimentalandcomputationalapproachestoestimatesolubili tyandpermeabilityindrugdiscoveryanddevelopmentsettings " .AdvDrugDelRev23:3-25.; LipinskiCA, LombardoF, DominyBW, FeeneyPJ.Experimentalandcomputationalapproachestoestimat esolubilityandpermeabilityindrugdiscoveryanddevelopments ettings.AdvDrugDelivRev2001; 46:3-26).
Natural products is generally considered to " as medicine " type compound.Overwhelming majority medicine comes from natural products or derivatives thereof.During-1994 years nineteen eighty-threes, have 520 kinds of medicines and go through by examining to go on the market, about 39% comes from natural products or derivatives thereof.At present, one of emphasis of medicament research and development finds uniqueness in natural products, has the compound structure of synthesis feasibility.Comparison Study known drug database (14,000 compound) and natural products database (26,000 Small-molecule compounds extract) find, known drug is very similar with the physical property of natural products, the two difference structurally mainly comprises: 1) known drug relatively, the structure of natural products is tending towards complicated, the many rings in natural drug and bridged bond structure more much more than known drug; 2) known drug contains more nitrogen-atoms, and natural products is then containing more oxygen atom; 3) molecular weight of natural products is relatively large.
The Chemoinformatics of current rise can be used for " as the medicine " property judging compound, world's pharmaceutical industry also wishes to utilize analysis and identification known drug, be in " as medicine " property parameter that clinical experimental stage drug candidate and natural products etc. generate determines " as medicine " property compound, to find activated compound (Hit) and lead compound (Lead) as soon as possible.
" as Types of Medicine " compound is the important means of the active compound structure seeking to possess lead compound speciality.How effectively to be combined closely by the biological space representated by the chemical space of compounds represented and albumen target is design successfully key, is also increase the kind of new compound and the key of number.How to be designed for the compound collection of high flux screening, making it to possess high benefit, high-quality, high-level efficiency then becomes a very important research topic.According to statistics, 5,120 drug discoveries evaluating-2000 Nian Jian U.S. in 1900 approval only have 52 kinds so-called " core texture ", the results show that the limitation that pharmaceutical industry compound is collected.
The mode adopted when designing " as Types of Medicine " compound mainly utilizes " fragment " (Fragment), " connection " (Linker), Structures of Natural Products and spatial form etc.Any compound is by " fragment " composition, and pharmaceutical chemical " fragment " is more partial to heterogeneous ring compound.By finding the statistics of known drug database, 12, in 383 known drug compounds, having 7521 known drug compounds and comprising heterogeneous ring compound structure, comprising 117 kinds of heterocyclic types altogether; To 28, find in 710 natural products monomers researchs, have 21,372 compounds comprise heterogeneous ring compound structure.Sometimes there is intersection between the concept of " connection " and " fragment ", can think that " connection " is exactly the part of " fragment ", but when forming compound, needing " connection " between " fragment " and forming compound.To 12,000 has the research of bioactive compound to show, the compound of more than 60% is combined into " fragment " by " connection " and is synthesized out.The result of statistical research 6808 kinds of Chinese medical extract monomers shows, has kind more than 200 to be simple compounds containing heterocycle, further transforms and modify these compound structures, will develop the medicine framework compound of several times.Should say, find out the emphasis that core texture is the medicine framework compound exploitation of natural products.Whether spatial form directly has influence on compound and can effectively act on biological target, as biological selectivity.Large quantifier elimination uses three-dimensional structural analysis to carry out the space structure of deterministic compound, but two-dimensional structure (matrix form) analysis can more intuitively, more simply for designing medicine framework compound.Regulate compound space structure to be one with different medicine framework compounds extremely effectively to screen reactive compound mode, be also the means that lead optimization is extremely commonly used.
The compound that may become medicine not only will have strong compatibility to specific biological target, also to have specific selectivity and acceptable ADME/T (absorption, distribution, metabolism, get rid of and toxicity) etc., these character are relevant for pharmacology toxic and side effect to its medicine.The key of SARS drug design is the biologically active that keeps even improving compound and selectivity, and makes it possess acceptable ADME/T character and clinical characteristics.How the factors affecting compound structure and characteristic is carried out comprehensively analyzing and assessment, the effective status reaching MOLECULE DESIGN is the technical matters that current medical research and development are badly in need of solving, and reaches the structural design originating from " as medicine " compound and the kind of active drug MOLECULE DESIGN.
Summary of the invention
In order to accelerate the process of medicament research and development, especially accelerating the process that domestic medicament research and development and the world integrate with, significantly improving the design efficiency of drug candidate, inventor's research obtains the Method and Technology platform that multi-dimensional matrix designs for medicine framework compound molecule.The matrix optimizing theory of mathematics is used in medicine and relevant MOLECULE DESIGN field thereof by this platform first, and by will a large amount of factors considered be needed in drug development process to carry out sorting out and contrasting according to certain characteristic, thus use a small amount of parameter to represent the parameter of enormous amount, to improve design efficiency and the synthesis benefit thereof of medicine framework compound molecule.
The theory of multi-dimensional matrix MOLECULE DESIGN is, any drug molecule is all combined by so-called compound basic structural unit, by to 3,000,000 kinds of high values " as medicine ' type compound carries out compound structure classification according to 28000 kinds of compound basic structural units; then carry out structure analysis; result shows, the mode of compound basic structural unit composition drug molecule presents arrangement, the array mode of matrix and multi-dimensional matrix.Meanwhile, the results of structural analysis of natural products and Effective Component of Chinese Medicine monomeric compound shows, basic structural unit and the array mode thereof of synthesis compound and natural products have similarity.Therefore, when SARS drug design, the various empirical data of novel drug candidate molecular structure and known compound structure are carried out Structure Comparison, greatly can improve specific aim and the validity of SARS drug design.
Multi-dimensional matrix MOLECULE DESIGN platform is that medicine and relevant MOLECULE DESIGN thereof provide the Structure Comparison of a systematized matrix pattern and the method for structure optimization.The method adopts multi-dimensional matrix arrangement, combination and the relevant variable of structural factor of cluster analysis compound and the relevant variable of variable factor, refer again to the Structure Comparison result of structural region and empirical data, optimize representative compound structure type, to reduce the compound amounts needing synthesis significantly, and the drug candidate with biologic activity or certain drug activity needed for obtaining fast, thus significantly improve design efficiency and the benefit of compound molecule.
The present invention adopts the compound structure type that market can provide to carry out the method for designing of medicine framework compound structure, and described method is achieved through the following technical solutions.
The object of the present invention is to provide a kind of method for designing of medicine framework compound structure, it is characterized in that, comprise the steps:
(1) available compound structure type on selected market, is mainly target setting with ring compound, is preferably heterocycle or non-assorted ring filling or undersaturated ring compound; And/or
(2) be fixed factor by compound structure type definition available on selected market, respectively with capitalization A, B, C, D...Y or Z are represented; And/or
(3) introduce any one or its combination of common functional group, substituting group or compound basic structural unit type, or with reference to and use the functional group or substituting group that have had; And/or
(4) mode of multi-dimensional matrix is adopted, by fixed factor A, B, C, any one or its of the common functional groups of D......Y or Z and introducing, substituting group or compound basic structural unit type combine or the functional group that had or substituting group combine, and the structure after combination is defined as A1, A2, A3, A4......, B1, B2, B3, B4......, C1, C2, C3, C4......, D1, D2, D3, D4......; And/or
(5) with reference to empirical data, select the variable factor and the variable thereof that affect compound, described variable factor is respectively with lowercase a, b, c, d...y or z are represented, the variable of described a is selected from a1, a2, a3...an, and the variable of described b is selected from b1, b2, b3...bn, and the variable of described c is selected from c1, c2, c3...cn, the variable of described y is selected from y1, y2, y3...yn, the variable of described z is selected from z1, z2, z3...zn, and the variable of described d is selected from d1, d2, d3...dn
Wherein, n is natural number; And/or
(6) by the A1... in step (4), B1..., C1..., D1... and empirical data variable factor a1..., b1..., c1..., d1... adopt the mode of multi-dimensional matrix to carry out Structure Comparison; And/or
(7) according to said structure contrast, the structure type of the newtype drug framework compound that optimization is representative, preferably uses A1a1, A1a2, A1a3...Aman, B1b1, B1b2, B1b3, B1b4......Bmbn, C1c1, C1c2, C1c3, C1c4...Cmcn, D1d1, D1d2, D1d3, D1d4...Dmdn represent, wherein, m, n are identical or different, represent natural number.
According to the preferred technical solution of the present invention, described method for designing also comprises arbitrary or Overall Steps as follows further:
(8) the representative newtype drug framework type of compounds of optimization and market information are carried out comparative evaluation, therefrom determine the newtype drug framework compound structure possessing value; And/or
(9) the medicine framework compound of above-mentioned generation is carried out combined crosswise, by A1a1...Aman and Bab1...Bmbn; B1b1...Bmbn and C1c1...Cmcn; C1c1...Cmcn and D1d1...Dmdn carries out intersection optimal combination, and wherein, m, n respectively represent natural number, can be identical or different; And/or
(10) according to said structure combined crosswise and the representative newtype drug framework compound structure type of optimization thereof, A1a1B1b1...AmanBmbn is used; B1b1C1c1...BmbnCmcn; C1c1D1d1...CmcnDmdn is representative, and wherein, m, n respectively represent natural number, can be identical or different; And/or
(11) the representative newtype drug framework type of compounds of optimization and market information are carried out contrasting and assessing, determine the newtype drug framework compound structure possessing value; And/or
(12) the medicine framework compound of above-mentioned generation is carried out combined crosswise, by A1a1B1b1...AmanBmbn and B1b1C1c1...BmbnCmcn; B1b1C1c1...BmbnCmcn and C1c1D1d1...CmcnDmdn carries out intersection optimal combination, and wherein, m, n respectively represent natural number, can be identical or different; And/or
(13) according to said structure combined crosswise and the representative newtype drug framework compound structure type of optimization thereof, A1a1B1b1C1c1...AmanBmbnCmcn is used; B1b1C1c1D1d1...BmbnCmcnDmdn is representative, and wherein, m, n respectively represent natural number, can be identical or different; And/or
(14) the representative newtype drug framework type of compounds of optimization and market information are carried out contrasting and assessing, determine the newtype drug framework compound structure possessing value.
According to optimal technical scheme of the present invention, described method for designing also comprises arbitrary or Overall Steps as follows further, and wherein, described method preferred pin carries out further structure optimization to by the medicine framework compound determined:
With reference to empirical data, select the variable factor and the variable thereof that affect drug candidate, described variable factor is respectively with lowercase a ', b ', c ', d ' ... y ' or z ' is represented, the variable of described a ' is selected from a1 ', a2 ', a3 ' ... an ', the variable of described b ' is selected from b1 ', b2 ', b3 ' ... bn ', the variable of described c ' is selected from c1 ', c2 ', c3 ' ... cn ', the variable of described d ' is selected from d1 ', d2 ', d3 ' ... dn ', the variable of variable factor y ' is selected from y ' 1, y ' 2, y ' 3...y ' n, the variable of variable factor z ' is selected from z ' 1, z ' 2, z ' 3...z ' n, wherein, n is natural number, consider the correlationship of structural region and variable factor, therefrom select representational structure type A ' B ', B ' C ', C ' D ' ... Y ' Z ', and/or
The structure type of the representative newtype drug framework compound of optimization is contrasted, with A1a1B1b1, A1a1B1b2 according to said structure, A1a1B1bn, A2a1B1b1......AmanBmbn, B1b1C1c1, B1b1C1c2 ... BmbnCmcn, C1c1D1d1, C1c1D1d2, ... CmcnDmdn is representative, wherein, and m, n respectively represents natural number, can be identical or different; And/or
By the representational structure type A ' B ', B ' C ', the C ' D ' that optimize ... Y ' Z ' with to its influential variable factor a ' b ', b ' c ', c ' d ' ... y ' z ' carries out Structure Comparison, draw the compound structure type A of optimization " B " C ", B " C " D " ... X " Y " Z "; wherein; structure type represents A ", B ", C ", D " ... X ", Y " or Z " by modifiable structural region A ', B ', C ', D ' ... Y ' or Z ' and variable factor a ', b ', c ', d ' ... y ' or z ' determines jointly; And/or
The structure type of the representative newtype drug framework compound of optimization is contrasted according to said structure, with A1a1B1b1C1c1, A1a1B1b1C1c2, A1a1B1b1C1cn, A2a1B1b1C1c1......AmanBmbnCmcn, B1b1C1c1D1d1, B1b1C1c1D1dn ... BmbnCmcnDmdn is representative, wherein, m, n respectively represent natural number, can be identical or different; And/or
According to optimize compound structure type A " B " C ", B " C " D " ... X " Y " Z " and with to its influential variable factor a " b " c ", b " c " d " ... x " y " z " carry out Structure Comparison, complete structural design and the optimization of drug candidate; And/or
The structure type of the representative newtype drug framework compound of optimization is contrasted according to said structure, with A1a1B1b1C1c1D1d1, A1a1B1b1C1c1D1d2, A1a1B1b1C1c1D1dn, A2a1B1b1C1c1D1d1......AmanBmbnCmcnDmdn is representative, wherein, and m, n respectively represents natural number, can be identical or different.
Optionally, according to the design needs of drug candidate, multi-dimensional matrix is adopted to repeat part or all of step in above-mentioned steps to carry out the process of textural association, structure analysis and structural confirmation, until obtain drug candidate structure type.
Wherein, described market information refers to compound structure type known on market; And drug candidate is target compound of the present invention.
Another object of the present invention is to the method for designing that a kind of medicine framework compound structure is provided, it is characterized in that, comprise the steps:
(1) available compound structure type on selected market, is mainly target setting with ring compound, is preferably heterocycle or non-assorted ring filling or unsaturated cyclic compounds; And/or
(2) be fixed factor by compound structure type definition available on selected market, respectively with capitalization A, B, C, D...Y or Z are represented; And/or
(3) at fixed factor A, in B, C, D...Y or Z, introduce substituting group or functional group, or use the functional group or substituting group that have had; And/or
(4) produce medicine framework compound structure, use A1...An; B1...Bn; C1...Cn; D1...Dn; ... Y1...Yn; Or Z1...Zn representative, wherein, n is natural number, and each n can be identical or different; And/or
(5) compound basic structural unit or connection is introduced, the compound basic structure newly introduced or connection are defined as variable factor or variable, described variable factor is respectively with lowercase a, b, c, d...y or z is represented, the variable of described a is selected from a1, a2, a3...an, the variable of described b is selected from b1, b2, b3...bn, the variable of described c is selected from c1, c2, c3...cn, the variable of described d is selected from d1, d2, d3...dn, the variable of described y is selected from y1, y2, y3...yn, the variable of described z is selected from z1, z2, z3...zn, wherein n is natural number, each n can be identical or different, and/or
(6) medicine framework compd A 1...An step (4) produced; B1...Bn; C1...Cn; D1...Dn, the compound basic structural unit introduced with step (5) or be connected a1, a2, a3...; B1, b2, b3...; C1, c2, c3...; D1, d2, d3..., carry out matrix form combined crosswise and Optimization analyses; And/or
(7) above-mentioned combined crosswise and Optimization analyses produce novel medicine framework compound: A1a1...Aman; B1b1...Bmbn; C1c1...Cmcn; D1d1...Dmdn; Wherein m, n are natural number, can be identical or different; And/or
(8) to the newtype drug framework compound of above-mentioned generation, matrix type structure comparative analysis is carried out for empirical data, the empirical data introduced, be thought of as new variable, represent with X, produce empirical data variable X1, X2...Xp, novel medicine framework compound: A1a1...Aman; B1b1...Bmbn; C1c1...CmcnD1d1...Dmdn; ... .. and empirical data variable X1, X2...Xp carry out matrix type structure contrast and Optimization analyses, and wherein m, n, p are natural number, can be identical or different; And/or
(9) said structure contrast and Optimization analyses produce newtype drug framework compound structure type: a1a1x1...Amanxp, and wherein m, n, p are natural number, can be identical or different; And/or
(10) the representative newtype drug framework type of compounds of optimization and market information are carried out comparative evaluation, determine the newtype drug framework compound structure possessing value.
Preferably, described method also comprises arbitrary or Overall Steps as follows further, and wherein said method preferred pin carries out further MOLECULE DESIGN to by the medicine framework compound determined:
With reference to empirical data, select the variable factor and the variable thereof that affect drug candidate, described variable factor is respectively with lowercase a ', b ', c ', d ' ... y ' or z ' is represented, the variable of described a ' is selected from a1 ', a2 ', a3 ' ... an ', the variable of described b ' is selected from b1 ', b2 ', b3 ' ... bn ', the variable of described c ' is selected from c1 ', c2 ', c3 ' ... cn ', the variable of described d ' is selected from d1 ', d2 ', d3 ' ... dn ', the variable of variable factor y ' is selected from y ' 1, y ' 2, y ' 3...y ' n, the variable of variable factor z ' is selected from z ' 1, z ' 2, z ' 3...z ' n, wherein n is natural number, consider the correlationship of structural region and variable factor, therefrom select representational structure type A ' B ', B ' C ', C ' D ' ... Y ' Z ', and/or
According to said structure contrast, the structure type of the newtype drug framework compound that optimization is representative, with A1a1B1b1, A1a1B1b2, A1a1B1bn, A2a1B1b1......AmanBmbn, B1b1C1c1, B1b1C1c2 ... BmbnCmcn, C1c1D1d1, C1c1D1d2 ... CmcnDmdn is representative, wherein m, n respectively represents natural number, can be identical or different; And/or
By the representational structure type A ' B ', B ' C ', the C ' D ' that optimize ... Y ' Z ' with to its influential variable factor a ' b ', b ' c ', c ' d ' ... y ' z ' carries out Structure Comparison, draws the compound structure type A of optimization " B " C ", B " C " D " ... X " Y " Z "; Wherein, structure type represents A ", B ", C ", D " ... X ", Y " or Z " by modifiable structural region A ', B ', C ', D ' ... Y ' or Z ' and variable factor a ', b ', c ', d ' ... y ' or z ' determines jointly; And/or
The structure type of the newtype drug framework compound that said structure contrast optimization is representative, with A1a1B1b1C1c1, A1a1B1b1C1c2, A1a1B1b1C1cn, A2a1B1b1C1c1......AmanBmbnCmcn, B1b1C1c1D1d1, B1b1C1c1D1dn ... BmbnCmcnDmdn is representative, wherein m, n respectively represents natural number, can be identical or different; And/or
By optimize compound structure type A " B " C ", B " C " D " ... X " Y " Z " and with to its influential variable factor a " b " c ", b " c " d " ... x " y " z " carry out Structure Comparison, complete structural design and the optimization of drug candidate; And/or
Contrast according to said structure, the structure type of the newtype drug framework compound that optimization is representative, with A1a1B1b1C1c1D1d1, A1a1B1b1C1c1D1d2, A1a1B1b1C1c1D1dn, A2a1B1b1C1c1D1d1......AmanBmbnCmcnDmdn are representative, wherein, m, n respectively represent natural number, can be identical or different; And/or
In the preferred technical solution of the present invention, can according to the design needs of drug candidate, the part or all of step adopting multi-dimensional matrix to repeat medicine framework compound design of the present invention to carry out the structure analysis of medicine framework compound, structural confirmation, structure optimization, until obtain the structure type with the medicine framework compound of required biologic activity or pharmacologically active.
At present, Field of Drug Discovery has basic structural unit, functional group and unit have kind more than 30000.These basic structure type clusters can be about 500 kinds by multi-dimensional matrix by the present invention, are 30-50 kind by conventional functional group cluster.
In the preferred technical solution of the present invention, described basic structural unit is selected from any one or its combination of saturated or undersaturated single ring architecture unit, twin nuclei unit, multiring structure unit.
In the preferred technical solution of the present invention, described single ring architecture unit is selected from any one or its combination of aromatic monocyclic, non-aromatic monocyclic, the aromatic monocyclic of replacement, the non-aromatic monocyclic of replacement.
In the preferred technical solution of the present invention, described twin nuclei unit is selected from any one or its combination of aromatic bicyclic, non-aromatic dicyclo, the aromatic bicyclic of replacement, the non-aromatic dicyclo of replacement.
In the preferred technical solution of the present invention, described multiring structure unit is selected from any one or its combination of fragrant many rings, non-aromatic many rings, the many rings of fragrance of replacement, non-aromatic many monocycles of replacement, and wherein, the number of rings of described multiring structure unit is no less than 3.
Substituting group of the present invention refers to the structural moiety of any compound, is selected from any one or its combination of alkyl, thiazolinyl, alkynyl, hydroxyl, ether, ester group, aryl, heteroaryl, naphthenic base, heterocyclic radical.
Functional group of the present invention is selected from any one or its combination of ketone, aldehyde, fat, amine, acid amides, singly-bound, double bond, triple bond, halogen, acid, alcohol, mercaptan, sulfonic acid, phenol, thiophenol.
In the preferred technical solution of the present invention, described empirical data be selected from target organisms activity, target organisms selectivity, cytoactive, toxic and side effect, ADME character, as the property of medicine, can synthetic any one or its combination.
In the preferred technical solution of the present invention, described empirical data are selected from any one or its combination of following database:
1) the compound structure types of database of protein target database and correspondence thereof is commonly used in international drugs research and development field; Or
2) the compound structure types of database that the conventional protein target of international drugs research and development is corresponding; Or
3) medicament research and development core texture database; Or
4) drug molecule framework type of compounds database; Or
5) what be verified has bioactive compound structure types of database; Or
6) the marketed drug database can inquired about; Or
7) bioequivalence type database; Or
8) metabolic type of compounds database; Or
9) toxic chemical structure type database; Or
10) Effective Component of Chinese Medicine type of compounds database; Or
11) natural products monomeric compound structural database; Or
12) medication data storehouse; Or
13) medical keyword database.
Another object of the present invention is to provide the application of multi-dimensional matrix in medicine framework compound structure type design, it is characterized in that, described multi-dimensional matrix arrangement is analyzed by structural region and empirical data and draws.
In the preferred technical solution of the present invention, adopt multi-dimensional matrix arrangement, combination and the relevant variable of structural factor of cluster analysis compound and the relevant variable of variable factor, refer again to the Structure Comparison result of structural region and empirical data, optimize the structure type of representative medicine framework compound.
According to the present invention, in medicine framework compound structure type design, method for designing of the present invention is adopted to carry out the design of medicine framework compound molecule.
In order to clear statement protection scope of the present invention, the present invention is explained and illustrated following term.
" ADME/T " of the present invention refers to the character that compound has in absorption, distribution, metabolism, excretion, toxicity etc.
Target of the present invention refers to the bioprotein certain indication being possessed to effect, can according to its biological effect, indication (as anticancer, heart disease, central nervous diseases etc.), target type (as GPCR, ion channel etc.) classification.Simultaneously, any biological target or protein all have some target spots, target spot corresponding to identical target also corresponding different biologically active or indication and play different effects, and same target spot only possesses effective especially active to a biological target or indication.
" target compound " of the present invention is also known as " reference compound ", " drug design target " or " object of reference ", comprise and known certain bioactive compound structure type is possessed for particular organisms target and target spot, namely known compound structure type.
" known compound structure type " of the present invention refers to disclosed in patent documentation or scientific and technical literature, have bioactive compound structure type for particular organisms target, comprises marketed drug, is in government department and declares the drug candidate of stage or clinical stage, be in the compound etc. in preclinical study stage.
In the preferred technical solution of the present invention, the approach of select target compound comprises any one or its combination of target corresponding to indication, indication, the target of the target be verified or widely accepted target or clear mechanism, target type or protein groups (as GPCR, ion channel etc.), the structure type of target proteins matter, patent documentation or the compound structure type disclosed in scientific and technical literature.
In the preferred technical solution of the present invention, described target compound is selected oneself the compound structure with particular organisms activity known, the compound structure inquired according to target code database or to particular target compounds effective structure type, any one or its combination of known drug or drug candidate, comprise marketed drug, be in the drug candidate of clinical stage, be in the drug candidate of preclinical study, lead compound, possesses bioactive natural products, traditional Chinese medicine monomer compound, Effective Component of Chinese Medicine, what be verified possesses bioactive picture property of medicine compound, Computeraided drug design (CADD designs compound), high flux screening compound, any one or its combination of the stereoeffect of known target proteins matter stereoeffect and target area thereof.
Reference object compound carries out the main R&D direction that SARS drug design is newtype drug, be about to carry out the analysis of compound structure molecule, design, transformation and optimization for the compound structure type of drone design, to obtain new compound structure type or type pilot compound structure type, also can be used for verifying biological target, and searching or designer drug compounds new construction (as Me-Too class medicine) etc.
Compound structure type of the present invention refers to series compound particular organisms target being possessed to biologically active and structural similarity.
Drug candidate of the present invention refers to the new compound structure (newchemicalentity, NCE) likely becoming marketed drug.
The analysis of the compound structure type ", determine and optimize " of the present invention refers to and adopts multi-dimensional matrix to arrange, to combine and cluster analysis affect drug candidate and can combine any one or its of druggability factor, realize effectively designing drug molecule with the Consideration of minimal number, the type pilot compound be optimized or the object of candidate drug compounds structure.
Target organisms of the present invention activity refers to the biologically active that compound has particular organisms target or cytoactive.
Target organisms selectivity of the present invention refers to the selectivity that the biologically active of the different target spot of compound on organism target has.
Cytoactive of the present invention refers to the biologically active of compound to specific cells.
Toxic and side effect of the present invention refers to the toxicity that compound has and/or spinoff.
Of the present inventionly syntheticly can refer to that compound possesses the feasibility that can be synthesized out.
" optimization of type pilot compound " of the present invention refers to that the compound one with particular organisms activity carries out structure optimization and properities optimization, to obtain the drug candidate possessing required biologically active or cytoactive.
Existing commercial compound database comprises following several:
1) comprehensive pharmaceutical chemistry database---ComprehensiveMedicinalChemistry (CMC);
2) international drugs database---WorldDrugIndex (WDI);
3) MDDR database;
4) class drug data base is investigated---InvestigationalDrugDatabase (IDDB);
5) commercial compound database---AvailableCompoundDatabse (ACD/SCD);
6) chemical guiding data storehouse---ChemNavigator
7) bioactive natural products database---BiologicallyActiveNaturalProducts (BDNP)
Therefore, those skilled in the art can retrieve and obtain target compound of the present invention from above-mentioned database.
In the preferred technical solution of the present invention, described target compound is known drug structure, is preferably widely used known drug on market, as antidiabetic medicine, cardiovascular drugs etc.
The present invention adopts the medical compounds structure be extensively examined clinically, carries out structure optimization and transformation for novel target, designs the novel medical compounds structure type for specific adaptations disease with effect, comprises type pilot type of compounds etc.
" empirical data " of the present invention are also known as " empirical parameter " or " test-type parameter ", refer to the data of accumulative experimental verification in medicament research and development history, described empirical data is selected from target organisms activity, target organisms selectivity, cytoactive, toxic and side effect, ADME character, the picture property of medicine, can synthetic or medicine for pharmaceutical parameter etc., the structure close association of these empirical data and compound, comprise the structure-activity relationship of compound, therefore, the aspects such as the Structure Comparison of comparison process inclusion compound of empirical data and the structure optimization of compound.
In the preferred technical solution of the present invention, described empirical data are selected from any one or its combination of following database:
1) the compound structure types of database of protein target database and correspondence thereof is commonly used in international drugs research and development field; Or
2) the compound structure types of database that the conventional protein target of international drugs research and development is corresponding; Or
3) medicament research and development core texture database; Or
4) drug molecule framework type of compounds database; Or
5) what be verified has bioactive compound structure types of database; Or
6) the marketed drug database can inquired about; Or
7) bioequivalence type database; Or
8) metabolic type of compounds database; Or
9) toxic chemical structure type database; Or
10) Effective Component of Chinese Medicine type of compounds database; Or
11) natural products monomeric compound structural database; Or
12) medication data storehouse; Or
13) medical keyword database etc.
Above-mentioned database is all databases known in the art, now exemplifies as follows:
The information that the compound database being in clinical stage is correlated with for the compound seeking to be in clinical stage, and the protein target information relevant to structure, comprise the discovery of target, the target be verified, protein structure and relative compound structure type thereof, its database representing type comprises:
http://thomsonscientific.jp/products/iddb/index.shtml；
http://www.cancer.gov/cancertopics/factsheet/Therapy/investigational-drug-access；
http://science.thomsonreuters.com/support/faq/sddb/；
http://www.centerwatch.com/drug-information/pipeline/；
http://www.pharmaprojects.com/research_development_analysis/tools.htm；
http://www.pipelinereview.com/store/product_info.php？products_id＝2741；
http://www.bioportfolio.com/store/product/7781/R-d-Drug-Pipeline-Database-2-months-Subsc ription.html；
http://thomsonreuters.com/products_services/science/science_products/a-z/pipeline_data_integ rator/；
http://www.ovid.com/site/catalog/DataBase/1244.jsp；
http://www.imshealth.com/portal/site/imshealth；
http://www.pjbpubs.com/；
http://www.fda.gov/。
ADME database is for studying, summing up the structural information relevant to character such as the absorption,distribution,metabolism,excretions of compound, and it represents type database and comprises:
http://www.pharmainformatic.com/html/adme_tox_predictions.html；
http://www.aureus-sciences.com/aureus/web/guest/adme-overview；
http://jp.fujitsu.com/group/kyushu/services/lifescience/english/asp/admedb/；
https://www.cloegateway.com/services/cloe_knowledge/paes/service_frontpage.php；
http://www.siritech.com/Cheminformatics.htm；
http://modem.ucsd.edu/adme/databases/databases_extend.htm；
http://www.pubpk.org/index.php？title＝Main_Page；
http://www.pubpk.org/index.php？title＝Main_Page；
http://www.hmdb.ca/；
http://www.nugo.org/metabolomics/36124；
http://www.genome.jp/kegg/pathway.html；
http://kanaya.naist.jp/KNApSAcK/；
http:// accelrys.com/products/databases/bioactivity/metabolite.h tmlwith
http://metlin.scripps.edu/。
Protein target database, for seeking the information with the protein target of disease association, comprises the discovery of target, the target be verified, protein structure and relative compound structure type thereof, and the database with the type of representative is as follows;
http://targetdb.pdb.org/
http://www.dddc.ac.cn/pdtd/
http://www.rcsb.org/pdb/home/home.do
http://bidd.nus.edu.sg/roup/CJTTD/TTD.asp
http://www.sciclips.com/sciclips/drug-targets-main.do
http://www.ncbi.nlm.nih.gov/genbank/
http://www.ebi.ac.uk/Databases/structure.html
Compou nd synthesis method database is for seeking synthetic method and the feasibility thereof of compound, and representative database is as follows:
https://scifinder.cas.org；
http:// accelrys.com/products/databases/synthesis/with
http://www.thieme-chemistry.com/en/products/joumals/synfacts.html。
Natural products and TCM Databases are for seeking the structured data of natural products and Chinese medicinal compound thereof, and representative database is as follows:
http://naturaldatabase.therapeuticresearch.com/home.aspx？cs＝&s＝ND；
http://www.ponderfodder.com/node/113；
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1347494/；
http://dnp.chemnetbase.com/intro/index.jsp；jsessionid＝80C9568C977F47200197BE48213AC5 1A；
http://www.heterocycles.jp/structure/structure.php；
http://www.chemnetbase.com/；
http://www.gfmer.ch/TMCAM/TNCAM_database_system.htm；
http://www.rmhiherbal.org/ai/pharintro.html；
http:// tcm.cmu.edu.tw/about01.php? menuid=1; With
http://tcm.cz3.nus.edu.sg/group/TCMsite/Default.aspx
" as medicine " type compound, have bioactive compound database for seeking " as medicine " type compound and having the information of bioactive compound, representative database is as follows:
http://accelrys.com/products/databases/bioactivity/mddr.html；
http://accelrys.com/products/databases/bioactivity/comprehensive-medicinal-chemistry.html；
http:// www.chemnavigator.com/with
http://accelrys.com/products/databases/sourcing/screening-compounds-directory.html。
Poisonous side effect of medicine database is for seeking the database of the characteristic such as toxicity, spinoff of compound, and its representative comprises:
http://databases.biomedcentral.com/browsesubject/？sub_id＝1013；
http://www.drugs.com/；
http://sideeffects.embl.de/；
http://www.pdrhealth.com/drugs/drugs-index.aspx；
http://www.drugs.com/drug_interactions.html；
http://www.pdrhealth.com/home/home.aspx；
http://www.rphworld.com/1ink-350.html；
http://toxnet.nlm.nih.gov/；
http://bioinf.xmu.edu.cn/databases/ADR/index.html；
http:// ctd.mdibl.org/with
http://accelrys.com/products/databases/bioactivity/toxicity.html。
Known drug database can provide the essential information of related drugs, and comprise protein target mechanism, drug molecular structure, medicine for information such as pharmacological properties, toxic and side effect, drug interactions, its representative comprises:
http://www.drugbank.ca/；
http://www.nlm.nih.gov/medlineplus/druginformation.html；
http://chrom.tutms.tut.ac.jp/JINNO/DRUGDATA/00database.html；
http://www.rxlist.com/script/main/hp.asp；
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/；
http://www.fda.gov/Drugs/InformationOnDrugs/ucm142438.htm；
http://www.ncbi.nlm.nih.gov/pubmed/；
http://www.webmd.com/；
http://www.3dchem.com/atoz.asp；
http:// www.drugs.com/with
http://www.pdrhealth.com/home/home.aspx。
Given data storehouse of the present invention provide a large amount of target compound in this area and can be for reference empirical data.
In the preferred technical solution of the present invention, adopt the structural confirmation first carrying out target compound during multi-dimensional matrix method design drug candidate, namely the molecular structure of compound is split according to molecular structure elementary cell, refer again to structure alignment analysis and the structure optimization result of empirical data, with seek minimum number changed region or can modified regions.
The compound structure type acting on biological target possesses specific structure parent nucleus more, this structure parent nucleus embodies the biologically active of compound for particular target, wherein, the space structure of compound structure parent nucleus should match with the spatial structure of target proteins matter, and the matching degree of the two is also determine the bioactive principal element of compound; Heteroatoms distribution on structure parent nucleus is relevant to the biological selectivity of compound; Functional group's distribution of structure parent nucleus is relevant with selectivity to its biologically active, and any heteroatoms and functional group all likely affect compound medicine in the distribution of compound structure is for performances such as, pharmacology and toxic and side effects.
In addition, different mother nucleus structure types has biologically active to a certain particular organisms target, and its determinative is space multistory molecular structure and the protein stereoeffect of compound.Therefore, the structured design process of compound need carry out molecular structure contrast, can refer to the scope of chemical engineered technology extension laminate structures contrast, and increases Consideration, to verify biological target further, and find new type pilot compound structure type.
When designing drug molecule, need to consider many factors, described Consideration comprise indication, biologically active, can synthetic, physicochemical property, stability, metabolism, medicine generation, pharmacology, toxicity any one or its combine.How effectively evaluate and analyze Correlative Influence Factors is the groundwork of drug design, and designing different objects of reference needs the influence factor of consideration or its order to there is difference, sometimes needs to turn over some influence factors.
When designing drug candidate based on target compound, should try one's best not change and even increase its biologically active and selectivity, and even improve its medicine for pharmacological properties by rational structural modification to improve, reduce its toxic and side effect, wherein, design needs Consideration to comprise:
A. protein target (also known as " biological target "); Or
B. the proofing state of target; Or
C. the compound structure type of particular target is acted on; Or
D. possessing of being verified is bioactive " as medicine " type compound structure type; Or
E. the compound structure type of known drug; Or
F. the compound structure type of the drug candidate of clinical investigation phase is in; Or
G. the compound structure type of the drug candidate in preclinical study stage is in; Or
H. the compound structure type of natural products; Or
I. the compound structure type of Effective Component of Chinese Medicine; Or
J. bioequivalence compound structure type; Or
K. metabolic thing structure type; Or
L. medicine is for pharmacological molecules structure type; Or
M. toxic chemical structure type; Or
N. basic compound structural unity type; Or
O. basic compound structure of functional groups type; Or
P. any one or its combination of synthesis mode.
In the preferred technical solution of the present invention, when needing to keep even improving biologically active and the selectivity of compound, the factor considered is needed to be selected from any one or its combination of A, B, C, D, E, F, G, H, I, K, P.
In the preferred technical solution of the present invention, when needing to keep even improving the space structure of compound, the factor considered is needed to be selected from any one or its combination of A, D, E, H, I, N, O, P.
In the preferred technical solution of the present invention, when needing to keep even improving compound metabolic, the factor of consideration is selected from any one or its combination of E, F, H, I, K, N, O, P.
In the preferred technical solution of the present invention, when the medicine needing to keep even improving compound is for pharmacological properties, the factor of consideration is selected from any one or its combination of D, E, F, G, H, I, L, P.
In the preferred technical solution of the present invention, when needing to reduce the toxic and side effect of compound, the factor of consideration is selected from any one or its combination of E, F, G, H, I, L, M, P.
When adopting the molecular structure of multi-dimensional matrix design compound, can any one or its combination of Consideration A-P separately, its objective is and effectively combine different factors, thus determine the structure type of target compound, and multi-dimensional matrix method can be adopted to carry out analysis of compounds structure.
In the preferred technical solution of the present invention, described target is 12000-15000 kind, it is derived from Genebank, TargetDB, ThreapueticTargetDB, DART, PDTD, TRMP, other Relational databases etc., comprise the target be verified, the target etc. be widely used, to determine the compound structure that target is corresponding, and design novel medical compounds structure type, novel type pilot type of compounds etc.
In the preferred technical solution of the present invention, described target compound is selected from the compound structure type from natural products or Effective Component of Chinese Medicine, can in conjunction with the characteristic of its conventional medicament, itself and target proteins matter structure are carried out Structure Comparison and structure optimization, find out effective new compound structure type or type pilot compound structure type, wherein, described natural products is derived from TheDirectoryofNaturalProduct, the databases such as TradionalChineseMedicineDatabas, NaturalProductDatabase.
In the preferred technical solution of the present invention, compounds effective structure type and biological target are carried out structure analysis and contrast, to seek possessing active new compound structure type to this biological target, wherein, described compounds effective is possess certain bioactive compound structure type through what verify, and in chemical space, represent the compound structure of maximum number, comprise natural products, and it is known, can inquire, derive from document and Relational database (comprises PubMed, CMC, MDDR, IDDB, Scifinder, Chemnivagator etc.) compound structure etc.
The method for designing of medicine framework compound of the present invention is intended to solve the design problem of synthesis " as Types of Medicine " compound, candidate drug compounds, medicine framework molecular structure of compounds required for medical compounds, make in medicament research and development MOLECULE DESIGN, affecting compound molecule biological property, physico-chemical property, ADME character, the aspects such as toxic and side effect character possess stronger specific aim, thus improve the efficiency of medicament research and development MOLECULE DESIGN.
The method for designing of medicine framework compound structure type of the present invention, creatively adopt multi-dimensional matrix and carry out structure analysis in conjunction with empirical data, structural confirmation, structural design and structure optimization, and comprehensive system have studied correlativity between medicine framework structure type and empirical data, significantly improve the specific aim of medicine framework compound structure type design, validity, comprehensive, systematicness, rationality and design efficiency, the intermediate needed for pharmaceutical synthesis or reagent are greatly enriched, and significantly shorten the time of medicament research and development, thus significantly reduce medicament research and development expense.
Accompanying drawing explanation
The medicine framework compound molecule design flow diagram of Fig. 1, a kind of technical scheme of the present invention.
The medicine framework compound molecule design flow diagram of Fig. 2, another kind of technical scheme of the present invention.
Wherein, the process flow diagram of Fig. 1 by preferred for the present invention method for designing with compound available on market for initial compounds has been described in detail, particular content is as follows:
(1) available compound structure type on selected market, is mainly target setting with ring compound, is preferably heterocycle or non-assorted ring filling or undersaturated ring compound; And/or
(2) be fixed factor by compound structure type definition available on selected market, respectively with capitalization A, B, C, D...Y or Z are represented; And/or
(3) introduce empirical data, select the variable factor and the variable thereof that affect compound, described variable factor is respectively with lowercase a, b, c, d...y or z are represented, the variable of described a is selected from a1, a2, a3...an, the variable of described b is selected from b1, b2, b3...bn, the variable of described c is selected from c1, c2, c3...cn, and the variable of described d is selected from d1, d2, d3...dn, wherein n is natural number; And/or
(4) fixed factor A that will be selected, B, C, D...... and empirical data variable factor or variable a1, a2, a3....; B1, b2, b3......; C1, c2, c3, c4......; D1, d2, d3, d4...... use multi-dimensional matrix mode to carry out Structure Comparison, the compound structure type that optimization is novel: A1a1, A1a2, A1a3......Aman, B1b1, B1b2, B1b3, B1b4......Bmbn, C1c1, C1c2, C1c3, C1c4......Cmcn, D1d1, D1d2, D1d3, D1d4......Dmdn, wherein m, n are natural number, and each subscript may be the same or different; And/or
(5) by the new compound structure type of optimization and common functional group, substituting group, any one or its combination of compound basic structural unit reasonably connect, produce the newtype drug framework compound structure type with functional group or substituting group and compound basic structural unit thereof: A1a1B1b1, A1a1B1b2, A1a1B1bn, A2a1B1b1......AmanBmbn, B1b1C1c1, B1b1C1c2, ... BmbnCmcn, C1c1D1d1, C1c1D1d2, ... CmcnDmdn is the newtype drug framework compound structure type of representative, m, n is natural number, and each subscript may be the same or different,
(6) by the new compound structure type of further optimization and common functional group, substituting group, any one or its combination of compound basic structural unit reasonably connect, produce the newtype drug framework compound structure type with functional group or substituting group and compound basic structural unit thereof: A1a1B1b1C1c1, A1a1B1b1C1c2, A1a1B1b1C1cn, A2a1B1b1C1c1......AmanBmbnCmcn, B1b1C1c1D1d1, B1b1C1c1D1dn, ... BmbnCmcnDmdn is the newtype drug framework compound structure type of representative, m, n is natural number, and each subscript may be the same or different,
(7) by the representative newtype drug framework type of compounds of optimization with carry out comparative evaluation for market information, determine the newtype drug framework compound structure possessing value.
In Fig. 2, be to introduce substituting group or group before or after carrying out multi-dimensional matrix with the key distinction of Fig. 1, therefore no longer describe in detail.
Embodiment
Below in conjunction with embodiment, the present invention is described further.It should be noted that, following embodiment can not as limiting the scope of the invention, and any improvement made on basis of the present invention is all without prejudice to spirit of the present invention.
It should be noted that, in following compound, the incomplete group of all chemical bonds all represents and to be connected with hydrogen.
Embodiment 1
Be that compound basic structural unit carries out the design of medicine framework compound molecule with the commercial available compound of 2-pyridine carboxylic acid (2-Pyridinecarboxylateacid), concrete steps are as follows:
(1) available compound structure type on selected market, with 2-pyridine carboxylic acid for compound basic structural unit carries out;
(2) selected above-claimed cpd structure type is defined as fixed factor, is represented with capitalization A respectively;
(3) introduce common functional group or substituting group or compound basic structural unit type, or with reference to and use the functional group or substituting group that have had;
According to the empirical data of related compound at Field of Drug Discovery, biological selectivity, toxic and side effect, poison type, ADME character, metabolism, bioequivalence, known drug, clinical medicine, as the property of medicine, can be synthetic etc. historical experience data carry out contrastive Analysis of Structures and optimization, produce the type following (as the type of the medicine framework compound selected, can determine according to demand, be below partial example wherein) of possible medicine framework compound:
Wherein, X=F, Cl, Br, I, CN, NO
2deng, R=alkyl, saturated or unsaturated ring, Y=O, NH, NR, S, SO, OSO, P etc.;
The compound structure more than designed, needs to carry out syntheticly can to utilize row assessment with business.
The example that part is concrete is as follows:
By the above-mentioned compound structure designed, carry out next step MOLECULE DESIGN, wherein functional group can be introduced, substituting group or basic compound structure type, it is according to adopting according to the empirical data of related compound at Field of Drug Discovery equally, biological selectivity, toxic and side effect, poison type, ADME character, metabolism, bioequivalence, known drug, clinical medicine, the picture property of medicine, can be synthetic etc. historical experience data carry out contrastive Analysis of Structures and optimization, the type producing possible medicine framework compound is following (as the type of the medicine framework compound selected, can determine according to demand, be below partial example wherein):
Wherein, X=F, Cl, Br, I, CN, NO
2deng, R=alkyl, saturated or unsaturated ring, Y=O, NH, NR, S, SO, OSO, P etc.;
The compound structure more than designed, after syntheticly can utilizing row assessment with business, filters out example as concrete in lower part:
By the above-mentioned compound structure designed, carry out next step MOLECULE DESIGN, wherein functional group can be introduced, substituting group or basic compound structure type, it is according to adopting according to the empirical data of related compound at Field of Drug Discovery equally, biological selectivity, toxic and side effect, poison type, ADME character, metabolism, bioequivalence, known drug, clinical medicine, the picture property of medicine, can be synthetic etc. historical experience data carry out contrastive Analysis of Structures and optimization, the type producing possible medicine framework compound is following (as the type of the medicine framework compound selected, can determine according to demand, be below partial example wherein):
Wherein, X=F, Cl, Br, I, CN, NO
2deng, R=alkyl, saturated or unsaturated ring, Y=O, NH, NR, S, SO, OSO, P etc.;
The compound structure more than designed, after syntheticly can utilizing row assessment with business, filters out example as concrete in lower part:
By the above-mentioned compound structure designed, carry out next step MOLECULE DESIGN, wherein functional group can be introduced, substituting group or basic compound structure type, it is according to adopting according to the empirical data of related compound at Field of Drug Discovery equally, biological selectivity, toxic and side effect, poison type, ADME character, metabolism, bioequivalence, known drug, clinical medicine, the picture property of medicine, can be synthetic etc. historical experience data carry out contrastive Analysis of Structures and optimization, the type producing possible medicine framework compound is following (as the type of the medicine framework compound selected, can determine according to demand, be below partial example wherein):
Wherein, X=F, Cl, Br, I, CN, NO
2deng, R=alkyl, saturated or unsaturated ring, Y=O, NH, NR, S, SO, OSO, P etc.;
The compound structure more than designed, after syntheticly can utilizing row assessment with business, filters out example as concrete in lower part:
Above any compound or series, all can use the mode of this multi-dimensional matrix to carry out cyclic design, carry out commercial availability assessment and analysis simultaneously in conjunction with business database.
Embodiment 2
Compound structural unity can be utilized to carry out the design of medicine framework compound molecule with business:
With 2-Pyridinecarboxylateacid---2-pyridine carboxylic acid, Toluene---toluene, Cyclopropylamine---cyclopropylamine, Piperazine---piperazine is that compound basic structural unit carries out the design of medicine framework compound molecule.
According to the empirical data of related compound at Field of Drug Discovery, biological selectivity, toxic and side effect, poison type, ADME character, metabolism, bioequivalence, known drug, clinical medicine, as the property of medicine, can be synthetic etc. historical experience data carry out contrastive Analysis of Structures and optimization, produce the type following (as the type of the medicine framework compound selected, determining according to demand, is below partial example wherein) of possible medicine framework compound:
Wherein, X=F, Cl, Br, I, CN, NO
2deng, R=alkyl, saturated or unsaturated ring, Y=O, NH, NR, S, SO, OSO, P etc.;
The compound structure more than designed, after syntheticly can utilizing row assessment with business, filters out example as concrete in lower part:
By the above-mentioned compound structure designed, carry out next step MOLECULE DESIGN, wherein functional group can be introduced, substituting group or basic compound structure type, it is according to adopting according to the empirical data of related compound at Field of Drug Discovery equally, biological selectivity, toxic and side effect, poison type, ADME character, metabolism, bioequivalence, known drug, clinical medicine, the picture property of medicine, can be synthetic etc. historical experience data carry out contrastive Analysis of Structures and optimization, the type producing possible medicine framework compound is following (as the type of the medicine framework compound selected, can determine according to demand, be below partial example wherein):
Wherein, X=F, Cl, Br, I, CN, NO2 etc., R=alkyl, saturated or unsaturated ring, Y=O, NH, NR, S, SO, OSO, P etc.;
The compound structure more than designed, after syntheticly can utilizing row assessment with business, filters out example as concrete in lower part:
By the above-mentioned compound structure designed, carry out next step MOLECULE DESIGN, wherein functional group can be introduced, substituting group or basic compound structure type, it is according to adopting according to the empirical data of related compound at Field of Drug Discovery equally, biological selectivity, toxic and side effect, poison type, ADME character, metabolism, bioequivalence, known drug, clinical medicine, the picture property of medicine, can be synthetic etc. historical experience data carry out contrastive Analysis of Structures and optimization, the type producing possible medicine framework compound is following (as the type of the medicine framework compound selected, can determine according to demand, be below partial example wherein):
Wherein, X=F, Cl, Br, I, CN, NO
2deng, R=alkyl, saturated or unsaturated ring, Y=O, NH, NR, S, SO, OSO, P etc.;
The compound structure more than designed, after syntheticly can utilizing row assessment with business, filters out example as concrete in lower part:
Wherein, X=F, Cl, Br, I, CN, NO
2deng, R=alkyl, saturated or unsaturated ring, Y=O, NH, NR, S, SO, OSO, P etc.;
Above any compound or series, all can use the mode of this multi-dimensional matrix to carry out cyclic design, carry out commercial availability assessment and analysis simultaneously in conjunction with business database.
Embodiment 3:
Be that compound basic structural unit carries out the design of medicine framework compound molecule with the commercial available compound of piperazine (RN:110-85-0), concrete steps are as follows:
(1) available compound structure type on selected market, with piperazine (RN:110-85-0) for compound basic structural unit carries out;
(2) selected above-claimed cpd structure type is defined as fixed factor, is represented with capitalization A;
(3) introduce common functional group or substituting group or compound basic structural unit type, or with reference to and use the functional group or substituting group that have had;
According to the empirical data of related compound at Field of Drug Discovery, biological selectivity, toxic and side effect, poison type, ADME character, metabolism, bioequivalence, known drug, clinical medicine, as the property of medicine, can be synthetic etc. historical experience data carry out contrastive Analysis of Structures and optimization, produce the type following (as the type of the medicine framework compound selected, can determine according to demand, be below partial example wherein) of possible medicine framework compound:
R1 is any substituted radical, as alkyl, and naphthenic base, carbonyl, the carbonyl of replacement, sulfoamido, alkyl amino sulfonyl etc.;
(4) according to the compound structure designed above, carry out syntheticly can to utilize row assessment with business.The example that part is concrete is as follows:
(5) by the above-mentioned compound structure designed, carry out next step MOLECULE DESIGN, wherein functional group can be introduced, substituting group or basic compound structure type, it adopts equally according to the empirical data of related compound at Field of Drug Discovery, and carries out syntheticly can to utilize row assessment with business.The example that part is concrete is as follows:
(6), after the framework compound of above-mentioned zone and nucleus being combined, according to the Structure Comparison result of each structural region and empirical data sequence, select representative compound structure type and verify.
Consider that the oxazolidinone antibiotics Linezoline of following structure is effective to many more obstinate gram-positive bacterias, comprise Vancomycin-resistant Enterococcus faecium, methicillin-resistant Staphylococcus aureus, penicillin resistance pneumococcus etc.The synthesis of the early stage anti-bacteria albumen that it can be transcribed at mRNA, absorbed following oral administration rapidly and completely.Many clinical research datas not yet delivered show, the pneumonia, skin infection, Vancomycin-resistant Enterococcus faecium etc. of linezolid to adult is all effective.
That thus abovementioned steps is designed is connected with nucleus B, relates to following structural compounds:
Wherein respectively substituently to be defined as follows:
X:NH, Y:CH; R1: cyclopropyl; R2: cyclopropyl.
Wherein, this compound such as following synthetic route is carried out:
By the compound that said method obtains, and by MIC Activity determination, this compound demonstrates the inhibition concentration index similar with Linezolid, and its result is that MIC50 (A) is between 1-1.5; MIC50 (B) is between 0.25-0.75.Wherein the antibacterial activity of compound uses MIC (MIC=minimuminhibitionconcentration:Lowestdrugconcentrati onforreducinggrowthby50%ormorw), uses Metthicillin-susceptibleStaphylococcus---to test A; Penicilin---suscepibleStreptococcuspneumonia---test b.The step of experiment is according to standard test procedure and method of testing, and the inhibition concentration standard of index is mcg/ml.
Claims (13)
1. a method for designing for medicine framework compound structure, is characterized in that, comprises the steps:
(1) available compound structure type on selected market, take ring compound as target setting;
(2) be fixed factor by compound structure type definition available on selected market, respectively with capitalization A, B, C, D ..., Z is represented;
(3) introduce any one or its combination of common functional group, substituting group or compound basic structural unit type, or with reference to and use the functional group or substituting group that have had;
(4) mode of multi-dimensional matrix is adopted, by fixed factor A, B, C, D ..., any one or its of the common functional groups of Z and introducing, substituting group or compound basic structural unit type combine or the functional group that had or substituting group combine, structure after combination is defined as A1, A2, A3, A4, ..., An; B1, B2, B3, B4 ..., Bn; C1, C2, C3, C4 ..., Cn, D1, D2, D3, D4 ..., Dn; Wherein n is natural number;
(5) with reference to empirical data, select to affect variable factor and the variable thereof of compound, described variable factor respectively with lowercase a, b, c, d, ..., z is represented, the variable of described a is a1, a2, a3 ..., the variable of an, described b is b1, b2, b3 ..., bn, the variable of described c is c1, c2, c3 ..., the variable of cn, described d is d1, d2, d3 ..., the variable of dn, described z is z1, z2, z3 ..., zn, wherein n is natural number;
(6) by the A1 in step (4), A2, A3, A4 ..., An; B1, B2, B3, B4 ..., Bn; C1, C2, C3, C4 ..., Cn; D1, D2, D3, D4 ..., Dn; With the variable a1 of empirical data variable factor, a2, a3 ..., an; B1, b2, b3 ..., bn; C1, c2, c3 ..., cn; D1, d2, d3 ..., dn ..., z1, z2, z3 ..., zn, adopts the mode of multi-dimensional matrix to carry out Structure Comparison;
(7) according to said structure contrast, the structure type of the newtype drug framework compound that optimization is representative, uses A1a1, A1a2, A1a3 ..., Aman; B1b1, B1b2, B1b3, B1b4 ..., Bmbn; C1c1, C1c2, C1c3, C1c4 ..., Cmcn; D1d1, D1d2, D1d3, D1d4 ..., Dmdn represents, and wherein, m represents natural number, and each m is identical or different, and n represents natural number, and each n is identical or different.
2. method for designing according to claim 1, described method for designing also comprises the steps: further
(8) structure type of the representative newtype drug framework compound of step (7) optimization and the close type of compounds of structure are carried out comparative evaluation, therefrom determine the newtype drug framework compound structure possessing value;
(9) the medicine framework compound structure of above-mentioned generation is carried out combined crosswise, by A1a1 ..., Anan and B1b1 ..., Bmbn; B1b1 ..., Bmbn and C1c1 ..., Cmcn; C1c1 ..., Cmcn and D1d1 ..., Dmdn carries out combined crosswise, and wherein, m represents natural number, and each m is identical or different, and n represents natural number, and each n is identical or different;
(10) according to the structure type of the representative newtype drug framework compound of said structure combined crosswise optimization, A1a1B1b1 is used ..., AmanBmbn; B1b1C1c1 ..., BmbnCmcn; C1c1D1d1 ..., CmcnDmdn is representative, and wherein, m and n is identical or different, represents natural number respectively;
(11) structure type of the representative newtype drug framework compound of step (10) optimization and close oneself of structure are known that type of compounds carries out contrasting and assessing, determine the newtype drug framework compound structure possessing value;
(12) the medicine framework compound structure of above-mentioned generation is carried out combined crosswise, by A1a1B1b1 ..., AmanBmbn and B1b1C1c1 ..., BmbnCmcn; B1b1C1c1 ..., BmbnCmcn and C1c1D1d1 ..., CmcnDmdn carries out combined crosswise, m and n is identical or different, represents natural number respectively;
(13) according to the structure type of the representative newtype drug framework compound of said structure combined crosswise optimization, A1a1B1b1C1c1 is used ..., AmanBmbnCmcn; B1b1C1c1D1d1 ..., BmbnCmcnDmdn is representative, and wherein, m and n is identical or different, represents natural number respectively;
(14) structure type of the representative newtype drug framework compound of optimization and market information are carried out contrasting and assessing, determine the newtype drug framework compound structure possessing value.
3. method for designing according to claim 1 and 2, described method for designing also comprises the steps: further
1) with reference to empirical data, select the variable factor and the variable thereof that affect newtype drug framework compound, described variable factor is respectively with lowercase a ', b ', c ', d ', ..., z ' is represented, the variable of described a ' is a1 ', a2 ', a3 ', ..., an ', the variable of described b ' is b1 ', b2 ', b3 ', ..., bn ', the variable of described c ' is c1 ', c2 ', c3 ', ..., cn ', the variable of described d ' is d1 ', d2 ', d3 ', ..., dn ', described z, variable be z1 ', z2 ', z3 ', ..., zn ', wherein, n is natural number, consider the correlationship of structural region and variable factor, the variable of described structural region is A ', B ', C ', D ' ..., Z ', therefrom selects representational structure type A ' B ', B ' C ', C ' D ' ..., Y ' Z ',
2) structure type of the representative newtype drug framework compound of optimization is contrasted according to said structure, with A1a1B1b1, A1a1B1b2, A1a1B1bn, A2a1B1b1 ..., AmanBmbn, B1b1C1c1, B1b1C1c2 ..., BmbnCmcn, C1c1D1d1, C1c1D1d2, ..., CmcnDmdn is representative, and wherein m represents natural number, each m is identical or different, and n represents natural number, and each n is identical or different;
3) representational structure type A ' B ', B ' C ', the C ' D ' that will optimize, ..., Y ' Z ' with to its influential variable factor a ' b ', b ' c ', c ' d ' ..., y ' z ' carries out Structure Comparison, draw the structure type A of the compound of optimization " B " C ", B " and C " D " ...; and X " Y " Z ", wherein, structure type represents A "; B ", C ", D ", ..., Z " by structural region A ', B '; C ', D ' ...; Z ' and variable factor a ', b ', c '; d ' ... y ', z ' jointly determine;
4) structure type of the representative newtype drug framework compound of optimization is contrasted according to said structure, with A1a1B1b1C1c1, A1a1B1b1C1c2, A1a1B1b1C1cn, A2a1B1b1C1c1 ..., AmanBmbnCmcn, B1b1C1c1D1d1, B1b1C1c1D1dn, ..., BmbnCmcnDmdn is representative, wherein, m represents natural number, each m is identical or different, and n represents natural number, and each n is identical or different;
5) according to the compound structure type A optimized " B " C ", B " and C " D " ...; and X " Y " Z " and to its influential variable factor a " b " c ", b " c " d " ...; and x " y " z " carry out Structure Comparison, complete structural design and the optimization of newtype drug framework compound;
6) structure type of the representative newtype drug framework compound of optimization is contrasted according to said structure, with A1a1B1b1C1c1D1d1, A1a1B1b1C1c1D1d2, A1a1B1b1C1c1D1dn, A2a1B1b1C1c1D1d1, ..., AmanBmbnCmcnDmdn is representative, wherein, m represents natural number, each m is identical or different, and n represents natural number, and each n is identical or different.
4. method for designing according to claim 1 and 2, is characterized in that, the ring compound in step (1) is selected from heterocycle or non-assorted ring filling or undersaturated ring compound.
5. method for designing according to claim 1 and 2, it is characterized in that, described method also comprises the design needs according to drug candidate, adopts multi-dimensional matrix to repeat above-mentioned steps to carry out the process of textural association, structure analysis and structural confirmation, until obtain drug candidate structure type.
6. a method for designing for medicine framework compound structure, is characterized in that, comprises the steps:
(1) available compound structure type on selected market, take ring compound as target setting;
(2) be fixed factor by compound structure type definition available on selected market, respectively with capitalization A, B, C, D..., Z are represented;
(3) at fixed factor A, in B, C, D..., Z, introduce substituting group or functional group, or use the functional group or substituting group that have had;
(4) obtain medicine framework compound structure, use A1 ..., An; B1 ..., Bn; C1 ..., Cn; D1 ..., Dn; ...; Z1 ..., Zn represents, and wherein, n is natural number, and n can be identical or different;
(5) compound basic structural unit or connection is introduced, the compound basic structural unit newly introduced or connection are decided to be variable factor or variable, described variable factor is respectively with lowercase a, b, c, d, ..., z is represented, the variable of described a is a1, a2, a3, ..., an, the variable of described b is b1, b2, b3, ..., bn, the variable of described c is c1, c2, c3, ..., cn, the variable of described d is d1, d2, d3, ..., dn, the variable of described z is z1, z2, z3, ..., zn, wherein, n is natural number, each n can be identical or different,
(6) medicine framework compound structure A1 step (4) produced ..., An; B1 ..., Bn; C1 ..., Cn; D1 ..., Dn, the compound basic structural unit introduced with step (5) or be connected a1, a2, a3 ..., an, b1, b2, b3 ..., bn, c1, c2, c3 ..., cn, d1, d2, d3 ..., dn, carries out matrix form combined crosswise and Optimization analyses;
(7) above-mentioned combined crosswise and Optimization analyses produce novel medicine framework compound: A1a1 ..., Aman; B1b1 ..., Bmbn; C1c1 ..., Cmcn; D1d1 ..., Dmdn; Wherein, m represents natural number, and each m is identical or different, and n represents natural number, and each n is identical or different;
(8) to the newtype drug framework compound of above-mentioned generation, carry out matrix type structure comparative analysis for empirical data, introduce empirical data, be thought of as new variable, represent with X, produce empirical data variable X1, X2 ..., Xp, medicine framework compound by novel: A1a1 ..., Aman; B1b1 ..., Bmbn; C1c1 ..., Cmcn; D1d1 ..., Dmdn; ... with empirical data variable X1, X2 ..., Xp carries out matrix type structure contrast and Optimization analyses, and wherein, m represents natural number, and each m is identical or different, and n represents natural number, and each n is identical or different, and p represents natural number, and each p is identical or different;
(9) said structure contrast and Optimization analyses produce the structure type of newtype drug framework compound: A1a1x1 ..., Amanxp, wherein, m represents natural number, and each m is identical or different, and n represents natural number, each n is identical or different, and p represents natural number, and each p is identical or different;
(10) structure type of the representative newtype drug framework compound of optimization and market information are carried out comparative evaluation, determine the newtype drug framework compound structure possessing value.
7. method for designing according to claim 6, is characterized in that, described method for designing also comprises the steps: further
With reference to empirical data, select the variable factor and the variable thereof that affect drug candidate, described variable factor is respectively with lowercase a ', b ', c ', d ', ..., z ' is represented, the variable of described a ' is a1 ', a2 ', a3 ', ..., an, , the variable of described b ' is b1 ', b2 ', b3 ', ..., bn ', the variable of described c ' is c1 ', c2 ', c3 ', ..., cn ', the variable of described d ' is d1 ', d2 ', d3 ', ..., dn ', the variable of described z ' is z ' 1, z ' 2, z ' 3, ..., z ' n, wherein, n is natural number, can be identical or different, consider the correlationship of structural region and variable factor, the variable of described structural region is A ', B ', C ', D ' ..., Z ', therefrom selects representational structure type A ' B ', B ' C ', C ' D ' ..., Y ' Z ',
According to said structure contrast, the structure type of the newtype drug framework compound that optimization is representative, with A1a1B1b1, A1a1B1b2, A1a1B1bn, A2a1B1b1 ..., AmanBmbn, B1b1C1c1, B1b1C1c2 ..., BmbnCmcn, C1c1D1d1, C1c1D1d2 ..., CmcnDmdn is representative, and wherein, m represents natural number, each m is identical or different, and n represents natural number, and each n is identical or different;
By representational structure type A ' B ', B ' C ', the C ' D ' that optimize, ..., Y ' Z ' with to its influential variable factor a ' b ', b ' c ', c ' d ', ..., y ' z ' carries out Structure Comparison, draws the compound structure type A of optimization " B " C ", B " and C " D ", ..., X " Y " Z "; Wherein, structure type represents A ", B ", C " and, D " ..., Z " by structural region A ', B ', C ', D ' ..., Z ' and variable factor a ', b ', c ', d ' ..., z ' determines jointly;
The structure type of the newtype drug framework compound that said structure contrast optimization is representative, with A1a1B1b1C1c1, A1a1B1b1C1c2, A1a1B1b1C1cn, A2a1B1b1C1c1 ..., AmanBmbnCmcn, B1b1C1c1D1d1, B1b1C1c1D1dn, ..., BmbnCmcnDmdn is representative, wherein, m represents natural number, each m is identical or different, and n represents natural number, and each n is identical or different;
Compound structure type A by optimizing " B " C ", B " and C " D " ..., X " Y " Z " and to its influential variable factor a " b " c ", b " c " d " ..., x " y " z " carry out Structure Comparison, complete structural design and the optimization of drug candidate;
According to said structure contrast, the structure type of the newtype drug framework compound that optimization is representative, with A1a1B1b1C1c1D1d1, A1a1B1b1C1c1D1d2, A1a1B1b1C1c1D1dn, A2a1B1b1C1c1D1d1 ..., AmanBmbnCmcnDmdn is representative, wherein, m represents natural number, and each m is identical or different, n represents natural number, and each n is identical or different;
Optionally, according to the design needs of drug candidate, multi-dimensional matrix is adopted to repeat above-mentioned steps to carry out the process of textural association, structure analysis and structural confirmation, until obtain drug candidate structure type.
8. the method for designing according to claim 6 or 7, is characterized in that, the ring compound in step (1) is selected from heterocycle or non-assorted ring filling or undersaturated ring compound.
9. the method for designing according to claim 1 or 6, is characterized in that,
Described basic structural unit is selected from any one or its combination of saturated or undersaturated single ring architecture unit, twin nuclei unit, multiring structure unit;
Described single ring architecture unit is selected from any one or its combination of aromatic monocyclic, non-aromatic monocyclic, the aromatic monocyclic of replacement, the non-aromatic monocyclic of replacement;
Described twin nuclei unit is selected from any one or its combination of aromatic bicyclic, non-aromatic dicyclo, the aromatic bicyclic of replacement, the non-aromatic dicyclo of replacement;
Described multiring structure unit is selected from any one or its combination of fragrant many rings, non-aromatic many rings, the many rings of fragrance of replacement, non-aromatic many rings of replacement, and wherein, the number of rings of described multiring structure unit is no less than 3;
Described substituting group refers to the structural moiety of any compound, is selected from any one or its combination of alkyl, thiazolinyl, alkynyl, hydroxyl, ether, ester group, aryl, heteroaryl, naphthenic base, heterocyclic radical;
Described functional group is selected from any one or its combination of ketone, aldehyde, fat, amine, acid amides, singly-bound, double bond, triple bond, halogen, acid, alcohol, mercaptan, sulfonic acid, phenol, thiophenol.
10. the method for designing according to claim 1 or 6, is characterized in that, described empirical data be selected from target organisms activity, target organisms selectivity, cytoactive, toxic and side effect, ADME character, as the property of medicine, can synthetic any one or its combination.
11. methods for designing according to claim 10, is characterized in that, described empirical data are selected from any one or its combination of following database:
1) the compound structure types of database of protein target database and correspondence thereof is commonly used in international drugs research and development field; Or
2) the compound structure types of database that the conventional protein target of international drugs research and development is corresponding; Or
3) medicament research and development core texture database; Or
4) drug molecule framework type of compounds database; Or
5) what be verified has bioactive compound structure types of database; Or
6) the marketed drug database can inquired about; Or
7) bioequivalence type database; Or
8) metabolic type of compounds database; Or
9) toxic chemical structure type database; Or
10) Effective Component of Chinese Medicine type of compounds database; Or
11) natural products monomeric compound structural database; Or
12) medication data storehouse; Or
13) medical keyword database.
12. multi-dimensional matrixes are arranged in the application in the design of medicine framework compound molecule, it is characterized in that, described multi-dimensional matrix arrangement is analyzed by structural region and empirical data and draws, adopt the method for any one of claim 1-11 to carry out the design of medicine framework compound structure, the variable of described structural region is A ', B ', C ', D ' ..., Z '.
13. application according to claim 12, it is characterized in that, adopt multi-dimensional matrix arrangement, combination and the relevant variable of fixed factor of cluster analysis compound and the relevant variable of variable factor, refer again to the Structure Comparison result of structural region and empirical data, the variable of described structural region is A ', B ', C ', D ' ..., Z ', optimizes the structure type of representative medicine framework compound.
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