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Drug Discovery: Design, Synthesis and Activity Evaluation

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: 31 January 2025 | Viewed by 2876

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Special Issue Editors

Dr. Joana L. C. Sousa

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Guest Editor

LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
Interests: heterocyclic compounds

Prof. Dr. Artur M. S. Silva

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Guest Editor

LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
Interests: organic chemistry; green synthetic organic chemistry; synthesis of heterocyclic compounds; natural products; NMR techniques; synthesis of new compounds with biocidal and antioxidant activities
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Special Issue Information

Dear Colleagues,

The Special Issue “Drug Discovery: Design, Synthesis and Activity Evaluation” aims at publishing studies within the medicinal chemistry field. In particular, it intends to cover the early stage of preclinical research in the drug discovery pipeline, including target identification and validation; hit discovery; assay development and screening; high-throughput screening; hit to lead; lead optimization; in vivo, in vitro and ex vivo assays; absorption, distribution, metabolism, and excretion (ADME); and drug delivery. Moreover, it welcomes not only original research papers, but also comprehensive reviews.

The original research papers should comprise the design (with or without computational support), organic synthesis, characterization, and biological activity evaluation of novel potent lead compounds, considering small to large biologically active molecules.

Dr. Joana L. C. Sousa
Prof. Dr. Artur M. S. Silva
Guest Editors

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Keywords

drug design
organic synthesis
biological activity evaluation
biologically active compounds
diagnostic/therapeutic agents
labeled ligands
structure–activity relationships (SARs)
structural biological studies
computational studies
pharmacokinetics/pharmacodynamics
drug delivery

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Published Papers (3 papers)

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Research

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29 pages, 5961 KiB

Open AccessArticle

Synthesis of Ethyl Pyrimidine-Quinolincarboxylates Selected from Virtual Screening as Enhanced Lactate Dehydrogenase (LDH) Inhibitors

by Iván Díaz, Sofía Salido, Manuel Nogueras and Justo Cobo

Int. J. Mol. Sci. 2024, 25(17), 9744; https://doi.org/10.3390/ijms25179744 - 9 Sep 2024

Viewed by 763

Abstract

The inhibition of the hLDHA (human lactate dehydrogenase A) enzyme has been demonstrated to be of great importance in the treatment of cancer and other diseases, such as primary hyperoxalurias. In that regard, we have designed, using virtual docking screening, a novel family of ethyl pyrimidine-quinolinecarboxylate derivatives (13–18)(a–d) as enhanced hLDHA inhibitors. These inhibitors were synthesised through a convergent pathway by coupling the key ethyl 2-aminophenylquinoline-4-carboxylate scaffolds (7–12), which were prepared by Pfitzinger synthesis followed by a further esterification, to the different 4-aryl-2-chloropyrimidines (VIII(a–d)) under microwave irradiation at 150–170 °C in a green solvent. The values obtained from the hLDHA inhibition were in line with the preliminary of the preliminary docking results, the most potent ones being those with U-shaped disposition. Thirteen of them showed IC₅₀ values lower than 5 μM, and for four of them (16a, 18b, 18c and 18d), IC₅₀ ≈ 1 μM. Additionally, all compounds with IC₅₀ < 10 μM were also tested against the hLDHB isoenzyme, resulting in three of them (15c, 15d and 16d) being selective to the A isoform, with their hLDHB IC₅₀ > 100 μM, and the other thirteen behaving as double inhibitors. Full article

(This article belongs to the Special Issue Drug Discovery: Design, Synthesis and Activity Evaluation)

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Figure 1

Figure 1
Examples of some reported double hLDHA and hLDHB, hLDHA selective, and hLDHB selective inhibitors with their corresponding IC50 values. Full article ">Figure 2
Overview of the previous pyrimidine-quinolones and current optimized ethyl pyrimidine-quinoline carboxylates. Full article ">Figure 3
Structural combination of the novel pyrimidine-quinoline hybrids for virtual screening selection. Full article ">Figure 4
Selected ethyl pyrimidine-quinolinecarboxylates for their synthesis. Full article ">Figure 5
Molecular structure of compound 16d, showing intramolecular hydrogen bonding. Full article ">Figure 6
Comparison of the poses of esters 13b (yellow), 14b (pink), 15b (blue), and reference W31 (black) in the hLDHA active site. The molecular surface around receptor atoms in the enzyme pocket has been represented in grey with green and red colors showing lipophilic and hydrophilic sites, respectively. Main amino acid residues have been labelled in yellow. Full article ">Figure 7
(a) Placement of compound 18c (yellow) and reference W31 (black) in the hLDHA active site. The molecular surface around receptor atoms in the enzyme pocket is represented in grey with green and red colors indicating lipophilic and hydrophilic sites, respectively. Main amino acid residues have been labelled in yellow. (b) 2D diagram of the ligand-protein interaction of compound 18c in the hLDHA active site. Full article ">Figure 8
2D diagram of the ligand-protein interaction of compounds 15b (a), 16c (b), 17c (c), and 18a (d) in the hLDHA active site. The hLDHA pocket has been represented with a grey dashed line. Full article ">Figure 9
Superposition of hLDHA 4R68 complex (ligand: W31, light red) and hLDHB 1I0Z complex (ligand: OXM, cyan). Arg106 residue of 1I0Z is labelled in purple. Arg105 residue of 4R68 is labelled blue. The other 4R68 and 1I0Z amino acid residues have been labelled in red and cyan, respectively. Full article ">Figure 10
(a) Placement of hybrids 15c (red), 15d (blue), and 16d (green) in the allosteric H1U site between chains A-C in 1I0Z. Amino acid chains have been represented with white sticks save for Glu214 and Lys310, which are represented in orange and have been labelled. (b) Placement of hybrids 15a (black) and 16a (yellow). Amino acid chains have been represented in orange (chain A) and blue (chain C). Amino acid residues of Glu214 and Lys310 have been labelled. Full article ">Scheme 1
Synthesis of aminophenylquinolin-4-carboxylic acids 1–6 as intermediates to pyrimidine-quinoline hybrids. Full article ">Scheme 2
Aminolysis reaction attempt to get pyrimidine-quinoline hybrid A by reaction of amino-phenylquinolin-4-carboxylic acid 1 and VIIIa. Full article ">Scheme 3
Esterification of aminophenylquinolin-4-carboxylic acids 1–6 to obtain the corresponding ethyl esters 7–12. Full article ">Scheme 4
Synthesis of pyrimidine-quinoline hybrids (13–15)a by aminolysis of 7–9 and VIIIa. Full article ">Scheme 5
General synthetic pathway to obtain the desired ethyl pyrimidine-quinolincarboxylates (13–18)(a–d) from isatins I–IV. Full article ">

15 pages, 4622 KiB

Open AccessArticle

Computational Design of Novel Cyclic Peptides Endowed with Autophagy-Inhibiting Activity on Cancer Cell Lines

by Marco Albani, Enrico Mario Alessandro Fassi, Roberta Manuela Moretti, Mariangela Garofalo, Marina Montagnani Marelli, Gabriella Roda, Jacopo Sgrignani, Andrea Cavalli and Giovanni Grazioso

Int. J. Mol. Sci. 2024, 25(9), 4622; https://doi.org/10.3390/ijms25094622 - 24 Apr 2024

Viewed by 1267

Abstract

(1) Autophagy plays a significant role in development and cell proliferation. This process is mainly accomplished by the LC3 protein, which, after maturation, builds the nascent autophagosomes. The inhibition of LC3 maturation results in the interference of autophagy activation. (2) In this study, starting from the structure of a known LC3B binder (LIR2-RavZ peptide), we identified new LC3B ligands by applying an in silico drug design strategy. The most promising peptides were synthesized, biophysically assayed, and biologically evaluated to ascertain their potential antiproliferative activity on five humans cell lines. (3) A cyclic peptide (named Pep6), endowed with high conformational stability (due to the presence of a disulfide bridge), displayed a K_d value on LC3B in the nanomolar range. Assays accomplished on PC3, MCF-7, and A549 cancer cell lines proved that Pep6 exhibited cytotoxic effects comparable to those of the peptide LIR2-RavZ, a reference LC3B ligand. Furthermore, it was ineffective on both normal prostatic epithelium PNT2 and autophagy-defective prostate cancer DU145 cells. (4) Pep6 can be considered a new autophagy inhibitor that can be employed as a pharmacological tool or even as a template for the rational design of new small molecules endowed with autophagy inhibitory activity. Full article

(This article belongs to the Special Issue Drug Discovery: Design, Synthesis and Activity Evaluation)

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Graphical abstract

Graphical abstract
Full article ">Figure 1
(A) LIR2-RavZ Cα atom RMSF plot (orange line). (B) Predicted binding mode of LIR2-RavZ (orange sticks) in complex with LC3B resulting at the end of MD simulations. The protein surface is colored depending on the atomic partial charges of the protein residues: blue for positive and red for negative charges, respectively. The H-bonds are represented as yellow dotted lines. Full article ">Figure 2
(A) Pep3 Cα atom RMSF plot (pink line) compared to LIR2-RavZ (orange line). Asterisks indicate the residues involved in the disulfide bond. (B) Predicted binding mode of Pep3 (pink sticks) in complex with LC3B resulting at the end of MD simulations. The protein surface is colored depending on the atomic partial charges of the protein residues: blue for positive and red for negative charges, respectively. The H-bonds are represented as yellow dotted lines. Full article ">Figure 3
(A) Effect of Pep3 on PC3 cell viability. Cell viability was determined using MTT assay after 24 h, 48 h, and 72 h. Six independent biological samples for each condition were analyzed (n = 6). Statistical analysis was performed using one-way ANOVA followed by Dunnett’s test (* p < 0.05 vs. CTRL; *** p < 0.001 vs. CTRL). (B) Western blot analysis of the LC3-II/LC3-I ratio in the PC3 cells treated with Pep3 (5 µM) or 3-methyladenine (3-MA) (1 mM). Full article ">Figure 4
(A) Pep6 Cα atom RMSF plot (red line) compared to LIR2-RavZ (orange line) and Pep3 (pink line). Asterisks indicate the residues involved in the disulfide bond. The D-amino acids of the Pep6 sequence are reported as lowercase letters. (B) Predicted binding mode of Pep6 (magenta sticks) in complex with LC3B resulting at the end of MD simulations. The protein surface is colored depending on the atomic partial charges of the protein residues: blue for positive and red for negative charges, respectively. The H-bonds are represented as yellow dotted lines. Full article ">Figure 5
(A) Effect of LIR2-RavZ and Pep6 on PC3 cell viability. Cell viability was determined using MTT assay after 72 h. Six independent biological samples for each condition were analyzed (n = 6). Statistical analysis was performed using one-way ANOVA followed by Dunnett’s test (** p < 0.01 vs. CTRL; *** p < 0.001 vs. CTRL). (B) Effect of LIR2-RavZ and Pep6 on DU145 cell viability. Cell viability was determined using MTT assay after 72 h. Six independent biological samples for each condition were analyzed (n = 6). Statistical analysis was performed using one-way ANOVA followed by Dunnett’s test. (C) Western blot analysis of LC3-II/LC3-I ratio and p62 in PC3 cells treated with LIR2-RavZ and Pep6. The relative optical density of LC3-I/tubulin, LC3-II/tubulin, and p62/tubulin was quantified using ImageJ software. The bar graph represents the mean ± SD calculated from three independent experiments. Statistical analysis was performed using one-way ANOVA followed by Dunnett’s post-test (*** p < 0.001 vs. CTRL). (D) Western blot analysis of LC3-II/LC3-I ratio in PC3 cells treated with Pep6 (5 µM) and trehalose (100 mM) for 48 h. The relative optical density of LC3-II/LC3-I was quantified using ImageJ software (version 1.50i). The bar graph represents the mean ± SD calculated from three independent experiments. Statistical analysis was performed using one-way ANOVA followed by Bonferroni’s post test (* p < 0.05 vs. CTRL). Full article ">Figure 6
Effect of LIR2-RavZ and Pep6 on cell viability. Cell viability was determined using MTS assay on PNT2 (A), A549 (B), and MCF-7 (C) 96 h post-treatment. Absorbance was measured with a 96-well plate spectrophotometer (Varioskan Flash Multimode Reader) at 490 nm (* p < 0.05 vs. CTRL; ** p < 0.01 vs. CTRL). Full article ">Figure 7
MST curves acquired using human recombinant His-tagged LC3B protein incubated with different concentrations of the control peptide LIR2-RavZ (A) and Pep6 (B), using the Monolith NT.115Pico instrument. Two independent experiments were performed to compute the Kd curve. Full article ">

Review

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16 pages, 1626 KiB

Open AccessReview

Comparison of Orthogonal Determination Methods of Acid/Base Constants with Meta-Analysis

by Tamás Pálla, Károly Mazák, Dania Mohammed Alkhazragee, György Tibor Balogh, Béla Noszál and Arash Mirzahosseini

Int. J. Mol. Sci. 2024, 25(23), 12727; https://doi.org/10.3390/ijms252312727 - 27 Nov 2024

Viewed by 244

Abstract

The accurate determination of acid/base constants (proton dissociation constants—pK_a, or equivalently protonation constants—logK) is essential for the physicochemical characterization of new molecules, especially in drug design and development, as these parameters thoroughly influence the pharmacokinetics and pharmacodynamics of drug action. While pH/potentiometric titration remains the gold standard method for determining acid/base constants, spectroscopic techniques—particularly nuclear magnetic resonance spectroscopy (as NMR/pH titrations)—have emerged as powerful alternatives for specific challenges in analytical chemistry, providing also information on the structure and site of protonation. In this study, we performed a comprehensive meta-analysis of protonation constants reported in the literature, measured using both potentiometry and NMR titrations. Our analysis compiled the available literature data and assessed the agreement between the two methods, taking into consideration various experimental conditions, such as temperature and ionic strength. The results provide insights into the reliability and applicability of NMR titrations compared with potentiometry, offering guidance for selecting appropriate methodologies in drug design. Full article

(This article belongs to the Special Issue Drug Discovery: Design, Synthesis and Activity Evaluation)

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