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Current virtual screening tools are fast, but reliable scoring is elusive. Here, we present the 'SQM/COSMO filter', a novel scoring function featuring a quantitative semiempirical quantum mechanical (SQM) description of all types of noncovalent interactions coupled with implicit COSMO solvation. We show unequivocally that it outperforms eight widely used scoring functions. The accuracy and chemical generality of the SQM/COSMO filter make it a perfect tool for late stages of virtual screening. Despite the enormous advances in method development for structure-based in silico drug design, reliable predictions of the structures (docking) and affinities (scoring) of protein–ligand (P–L) complexes still remain an unsolved task. 1 A plethora of scoring functions (SFs) have been devised by utilising experimental data for regression analyses, by constructing knowledge-based potentials, or based on physical laws. 2,3 As none of the SFs is general enough to perform equally strongly for a diverse set of P–L complexes, utilising several SFs at once (consensus scoring) holds promise. 4 Regression analysis and knowledge-based approaches to scoring are trained on a set of P–L complexes and rely on variable master equation terms. Their validity is limited to complexes similar to the training set. In principle, this problem has been overcome in physics-based methods. Because of computational cost, preference has been given to molecular mechanics (MM) methods, such as the combination of MM interaction energies with implicit solvation free energy terms (generalised Born, GB, or Poisson–Boltzmann, PB) to estimate affinities. 2 Additionally, the wide coverage of organic chemical space in the GAFF (general AMBER force field) 5 has made the parameterisation of ligands for MM straightforward. However, an explicit description of quantum mechanical (QM) effects in P–L interactions, such as charge transfer, polarisa-tion, covalent-bond formation or s-hole bonding, was missing. QM methods, which describe these effects qualitatively better than the energy functions used in MM-based SFs, were thus introduced into computational drug design. 6,7 Recent developments in QM methods and algorithms as well as the availability of a powerful computing infrastructure have paved the way to apply them for P–L complexes in numerous setups: linear scaling or efficient parallelisation of semi-empirical QM (SQM) methods, 7–10 QM/MM, 7,8,11,12 DFT-D3 on truncated P–L complexes 13 or various fragmentation methods. 11,14 Specifically, AM1, RM1, PM6 or DF–TB SQM methods have been used 7–9,12,15 as such or with empirical corrections for dispersion, hydrogen-and halogen-bonding 16 to describe the P–L noncovalent interactions. Merz et al. pioneered this area by introducing a QM-based SF (QMScore), a combination of the AM1 SQM method with an empirical dispersion (D) and the PB implicit solvent [eqn (1)]. 17 The method was useful for describing metalloprotein–ligand binding, but further corrections were needed, especially for a quantitative treatment of dispersion and hydrogen bonding. 10 Score = DE int + DDG solv + DG 0w conf À TDS (1) The above equation is a general physics-based SF. The terms are the gas-phase interaction energy (DE int), the change of solvation free energy upon complex formation (DDG solv), the change of conformational 'free' energy (DG 0w conf) and the change of entropy upon ligand binding (ÀTDS). Our approach is systematic. Using accurate calculations in small model systems as a benchmark, we developed corrections for SQM methods that provide reliable and accurate description of a wide range of noncovalent interactions including dispersion , hydrogen-and halogen-bonding. 16 Coupled with the PM6 SQM method, 18 the resulting PM6-D3H4X approach is applicable to a wide chemical space and does not require any
Journal of Computer-Aided Molecular Design
Transferable scoring function based on semiempirical quantum mechanical PM6-DH2 method: CDK2 with 15 structurally diverse inhibitors2011 •
The Journal of Physical Chemistry B
Semiempirical Quantum Mechanical Method PM6-DH2X Describes the Geometry and Energetics of CK2-Inhibitor Complexes Involving Halogen Bonds Well, While the Empirical Potential Fails2011 •
The Journal of Physical Chemistry B
Quantum Mechanics-Based Scoring Rationalizes the Irreversible Inactivation of Parasitic Schistosoma mansoni Cysteine Peptidase by Vinyl Sulfone Inhibitors2013 •
2015 •
Tuberculosis, the second leading infectious disease killer after HIV, remains a top public health priority. The causative agent of tuberculosis, Mycobacterium tuberculosis (Mtb), which can cause both acute and clinically latent infections, reprograms metabolism in response to the host niche. Phosphoenolpyruvate carboxykinase (Pck) is the enzyme at the center of the phosphoenolpyruvate-pyruvate-oxaloacetate node, which is involved in regulating the carbon flow distribution to catabolism, anabolism, or respiration in different states of Mtb infection. Under standard growth conditions, Mtb Pck is associated with gluconeogenesis and catalyzes the metal-dependent formation of phosphoenolpyruvate. In non-replicating Mtb, Pck can catalyze anaplerotic biosynthesis of oxaloacetate. Here, we present insights into the regulation of Mtb Pck activity by divalent cations. Through analysis of the X-ray structure of Pck-GDP and Pck-GDP-Mn2+ complexes, mutational analysis of the GDP binding site, an...
BioMed Research International
Application of Molecular Modeling to Urokinase Inhibitors Development2014 •
2013 •
Journal of medicinal chemistry
Large-scale validation of a quantum mechanics based scoring function: predicting the binding affinity and the binding mode of a diverse set of protein-ligand complexes2005 •
Computational methods to calculate binding affinity in protein-ligand interaction are of immense interest because of obvious practical applications in structure-based drug design. Scoring functions attempt to calculate the variation in binding affinity of ligands-inhibitors bound to protein targets at various levels of theory. In this study we use semiempirical quantum mechanics to design a scoring function that can calculate the electrostatic interactions and solvation free energy expected during complexation. This physically based approach has the ability to capture binding affinity trends in a diverse range of protein-ligand complexes. We also show the predictive power of this scoring function within protein targets and its ability to score ligand poses docked to a protein target. We also demonstrate the ability of this scoring function to discriminate between native and decoy poses and highlight the crucial role played by electrostatic interactions in molecular recognition. Fina...
Chemical Biology & Drug Design
Comparison of the Molecular Dynamics and Calculated Binding Free Energies for Nine FDA-Approved HIV-1 PR Drugs Against Subtype B and C-SA HIV PR2013 •
Current Topics in Medicinal Chemistry
GAMESS As a Free Quantum-Mechanical Platform for Drug Research2012 •
Journal of Computer-Aided Molecular Design
The SAMPL4 host–guest blind prediction challenge: an overview2014 •
Advances in carbohydrate chemistry and biochemistry
Carbohydrate-protein interactions: molecular modeling insights2014 •
Drug Discovery Today
The role of quantum mechanics in structure-based drug design2007 •
Chemical Reviews
Integrated Approach to Structure-Based Enzymatic Drug Design: Molecular Modeling, Spectroscopy, and Experimental Bioactivity2014 •
Journal of Physical Chemistry B
Anthramycin−DNA Binding Explored by Molecular Simulations2006 •
Journal of chemical theory and computation
Parametrization of an Orbital-Based Linear-Scaling Quantum Force Field for Noncovalent Interactions2014 •
Journal of Chemical Information and Modeling
Quantum Mechanical Pairwise Decomposition Analysis of Protein Kinase B Inhibitors: Validating a New Tool for Guiding Drug Design2010 •
Theoretical biology & medical modelling
Mathematical and computational modeling in biology at multiple scales2014 •
Journal of Medicinal Chemistry
Validation and Use of the MM-PBSA Approach for Drug Discovery2005 •
Journal of Computational Chemistry
Integrated Modeling Program, Applied Chemical Theory (IMPACT)2005 •
British Journal of Pharmacology
Towards the development of universal, fast and highly accurate docking/scoring methods: a long way to go2009 •
Molecular Simulation
Investigation into mechanism of orotidine 5′-monophosphate decarboxylase enzyme by MM-PBSA/MM-GBSA and molecular docking2014 •
Journal of Molecular Biology
Rescoring Docking Hit Lists for Model Cavity Sites: Predictions and Experimental Testing2008 •
Journal of Medicinal Chemistry
Novel 1-Hydroxypiperazine-2,6-diones as New Leads in the Inhibition of Metalloproteinases2011 •
Journal of Medicinal Chemistry
Binding Affinity Prediction for Ligands and Receptors Forming Tautomers and Ionization Species: Inhibition of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2)2012 •
Journal of Chemical Theory and Computation
Balance of Attraction and Repulsion in Nucleic-Acid Base Stacking: CCSD(T)/Complete-Basis-Set-Limit Calculations on Uracil Dimer and a Comparison with the Force-Field Description2009 •
Biophysical Journal
Sliding of Alkylating Anticancer Drugs along the Minor Groove of DNA: New Insights on Sequence Selectivity2008 •
Journal of Enzyme Inhibition and Medicinal Chemistry
Biological and computational evaluation of resveratrol inhibitors against Alzheimer’s disease2015 •
The Journal of Physical Chemistry A
Assessing the Role of Polarization in Docking2008 •
The Journal of Physical Chemistry B
Optimization of an AMBER Force Field for the Artificial Nucleic Acid, LNA, and Benchmarking with NMR of L(CAAU)2014 •
2013 •
Journal of Medicinal Chemistry
Automated Docking Screens: A Feasibility Study2009 •
European Journal of Medicinal Chemistry
Molecular modeling toward selective inhibitors of dihydrofolate reductase from the biological warfare agent Bacillus anthracis2015 •
Journal of Chemical Information and Modeling
Docking Ligands into Flexible and Solvated Macromolecules. 6. Development and Application to the Docking of HDACs and other Zinc Metalloenzymes Inhibitors2014 •
Journal of Medicinal Chemistry
Structural Basis for Inhibition of Mycobacterial and Human Adenosine Kinase by 7-Substituted 7-(Het)aryl-7-deazaadenine Ribonucleosides2014 •
Journal of Medicinal Chemistry
Docking Performance of Fragments and Druglike Compounds2011 •
Journal of Medicinal Chemistry
Hierarchy of Simulation Models in Predicting Structure and Energetics of the Src SH2 Domain Binding to Tyrosyl Phosphopeptides2002 •
Journal of Alloys and Compounds
First principles calculations of thermodynamic and mechanical properties of high temperature bcc Ta–W and Mo–Ta alloys2008 •
Biosensors and Bioelectronics
Towards the design of highly selective recognition sites into molecular imprinting polymers: A computational approach2006 •
Journal of Chemical Theory and Computation
pH Dependence of a 3 10 -Helix versus a Turn in the M-Loop Region of PDE4: Observations on PDB Entries and an Electronic Structure Study2008 •