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Hit Generation and Verification for Novel Lead Compounds

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 June 2018) | Viewed by 44366

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Dr. Jóhannes Reynisson

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School of Pharmacy, Keele University, Newcastle-under-Lyme ST5 5BG, UK
Interests: drug discovery; virtual screening; molecular modelling; chemical space; density functional theory
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Special Issue Information

Dear Colleagues,

Identifying quality hit compounds in drug discovery projects is a crucial step towards a clinical candidate. Without viable hits against the chosen target, no further progress can be made. A host of approaches have been developed to generate hits, e.g., various screening technologies, as well as traditional bioprospecting. After a hit has been found, a preliminary structure activity relationship (SAR) needs to be established against the target using biochemical and/or biophysical assays. Ligands can either be procured from commercially available compound collections using similarity methods or synthesized. Furthermore, the ligands must lie in a favorable region of chemical space. The SAR results can be checked using molecular modelling against the crystal structure of the target. Finally, cell-based assays are used to test the efficacy of the ligands verifying that their target can be modulated with a small molecule and indeed effects a desirable biological response such as apoptosis for anticancer drug development, i.e., the target is druggable.

A linear process is described here but more often than not it is very convoluted, e.g., the hypothesised target does not respond to the ligands but an excellent efficacy is observed in cell based assays or the activity of the hit is found in a cell based screen and the target needs to be identified. To complicate the process even further, many ligands modulate a host of different targets and finally the nebulous concepts of serendipity needs, somehow, to be considered.

In this Special Issue we wish to focus on the area in drug discovery where hits are identified and verified creating viable leads, laying the foundation for successful development of drug candidates.

Dr. Jóhannes Reynisson FRSC
Guest Editor

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Keywords

Screening – high throughput; virtual; fragment based
Similarity searching
Synthesis
Chemical space
Structural activity Relationship (SAR)
Biochemical assays
Biophysical assays
Cell based assays
Druggability

Published Papers (10 papers)

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Editorial

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3 pages, 582 KiB

Open AccessEditorial

Generation of Quality Hit Matter for Successful Drug Discovery Projects

by Jóhannes Reynisson

Molecules 2019, 24(3), 381; https://doi.org/10.3390/molecules24030381 - 22 Jan 2019

Viewed by 2694

Abstract

A drug discovery project needs a number of components for its success [...] Full article

(This article belongs to the Special Issue Hit Generation and Verification for Novel Lead Compounds)

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Research

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18 pages, 6077 KiB

Open AccessFeature PaperArticle

Structure-Based Identification of Potent Natural Product Chemotypes as Cannabinoid Receptor 1 Inverse Agonists

by Pankaj Pandey, Kuldeep K. Roy, Haining Liu, Guoyi Ma, Sara Pettaway, Walid F. Alsharif, Rama S. Gadepalli, John M. Rimoldi, Christopher R. McCurdy, Stephen J. Cutler and Robert J. Doerksen

Molecules 2018, 23(10), 2630; https://doi.org/10.3390/molecules23102630 - 13 Oct 2018

Cited by 15 | Viewed by 5503

Abstract

Natural products are an abundant source of potential drugs, and their diversity makes them a rich and viable prospective source of bioactive cannabinoid ligands. Cannabinoid receptor 1 (CB1) antagonists are clinically established and well documented as potential therapeutics for treating obesity, obesity-related cardiometabolic disorders, pain, and drug/substance abuse, but their associated CNS-mediated adverse effects hinder the development of potential new drugs and no such drug is currently on the market. This limitation amplifies the need for new agents with reduced or no CNS-mediated side effects. We are interested in the discovery of new natural product chemotypes as CB1 antagonists, which may serve as good starting points for further optimization towards the development of CB1 therapeutics. In search of new chemotypes as CB1 antagonists, we screened the in silico purchasable natural products subset of the ZINC12 database against our reported CB1 receptor model using the structure-based virtual screening (SBVS) approach. A total of 18 out of 192 top-scoring virtual hits, selected based on structural diversity and key protein–ligand interactions, were purchased and subjected to in vitro screening in competitive radioligand binding assays. The in vitro screening yielded seven compounds exhibiting >50% displacement at 10 μM concentration, and further binding affinity (K_i and IC₅₀) and functional data revealed compound 16 as a potent and selective CB1 inverse agonist (K_i = 121 nM and EC₅₀ = 128 nM) while three other compounds—2, 12, and 18—were potent but nonselective CB1 ligands with low micromolar binding affinity (K_i). In order to explore the structure–activity relationship for compound 16, we further purchased compounds with >80% similarity to compound 16, screened them for CB1 and CB2 activities, and found two potent compounds with sub-micromolar activities. Most importantly, these bioactive compounds represent structurally new natural product chemotypes in the area of cannabinoid research and could be considered for further structural optimization as CB1 ligands. Full article

(This article belongs to the Special Issue Hit Generation and Verification for Novel Lead Compounds)

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23 pages, 4909 KiB

Open AccessArticle

Fragment-Based Lead Generation of 5-Phenyl-1H-pyrazole-3-carboxamide Derivatives as Leads for Potent Factor Xia Inhibitors

by Qunchao Wei, Zhichao Zheng, Shijun Zhang, Xuemin Zheng, Fancui Meng, Jing Yuan, Yongnan Xu and Changjiang Huang

Molecules 2018, 23(8), 2002; https://doi.org/10.3390/molecules23082002 - 10 Aug 2018

Cited by 6 | Viewed by 3523

Abstract

FXIa is suggested as a major target for anticoagulant drug discovery because of reduced risk of bleeding. In this paper, we defined 5-phenyl-1H-pyrazole-3-carboxylic acid derivatives as privileged fragments for FXIa inhibitors’ lead discovery. After replacing the (E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylamide moiety in compound 3 with 5-(3-chlorophenyl)-1H-pyrazole-3-carboxamide, we traveled from FXIa inhibitor 3 to a scaffold that fused the privileged fragments into a pharmacophore for FXIa inhibitors. Subsequently, we synthesized and assessed the FXIa inhibitory potency of a series of 5-phenyl-1H-pyrazole-3-carboxamide derivatives with different P1, P1′ and P2′moiety. Finally, the SAR of them was systematically investigated to afford the lead compound 7za (FXIa Ki = 90.37 nM, 1.5× aPTT in rabbit plasma = 43.33 μM) which exhibited good in vitro inhibitory potency against FXIa and excellent in vitro coagulation activities. Furthermore, the binding mode of 7za with FXIa was studied and the results suggest that the 2-methylcyclopropanecarboxamide group of 7za makes 2 direct hydrogen bonds with Tyr58B and Thr35 in the FXIa backbone, making 7za binds to FXIa in a highly efficient manner. Full article

(This article belongs to the Special Issue Hit Generation and Verification for Novel Lead Compounds)

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15 pages, 2939 KiB

Open AccessArticle

A High-Content Screen Reveals New Small-Molecule Enhancers of Ras/Mapk Signaling as Probes for Zebrafish Heart Development

by Manush Saydmohammed, Laura L. Vollmer, Ezenwa O. Onuoha, Taber S. Maskrey, Gregory Gibson, Simon C. Watkins, Peter Wipf, Andreas Vogt and Michael Tsang

Molecules 2018, 23(7), 1691; https://doi.org/10.3390/molecules23071691 - 11 Jul 2018

Cited by 7 | Viewed by 4749

Abstract

Zebrafish is the preferred vertebrate model for high throughput chemical screens to discover modulators of complex biological pathways. We adapted a transgenic zebrafish line, Tg(dusp6:EGFP), which reports on fibroblast growth factor (Fgf)/Ras/Mapk activity, into a quantitative, high-content chemical screen to identify novel Fgf hyperactivators as chemical probes for zebrafish heart development and regeneration. We screened 10,000 compounds from the TimTec ActiProbe library, and identified several structurally distinct classes of molecules that enhanced Fgf/Ras/Mapk signaling. We chose three agents—ST020101, ST011282, and ST006994—for confirmatory and functional studies based on potency, repeatability with repurchased material, favorable whole organism toxicity, and evidence of structure–activity relationships. Functional follow-up assays confirmed that all three compounds induced the expression of Fgf target genes during zebrafish embryonic development. Moreover, these compounds increased cardiac progenitor populations by effecting a fate change from endothelial to cardiac progenitors that translated into increased numbers of cardiomyocytes. Interestingly, ST006994 augmented Fgf/Ras/Mapk signaling without increasing Erk phosphorylation, suggesting a molecular mechanism of action downstream of Erk. We posit that the ST006994 pharmacophore could become a unique chemical probe to uncover novel mechanisms of Fgf signaling during heart development and regeneration downstream of the Mapk signaling node. Full article

(This article belongs to the Special Issue Hit Generation and Verification for Novel Lead Compounds)

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18 pages, 4515 KiB

Open AccessArticle

A Novel Class of Cationic and Non-Peptidic Small Molecules as Hits for the Development of Antimicrobial Agents

by Aranza Jiménez, Pablo García, Sofia De la Puente, Andrés Madrona, María José Camarasa, María-Jesús Pérez-Pérez, José-Carlos Quintela, Francisco García-del Portillo and Ana San-Félix

Molecules 2018, 23(7), 1513; https://doi.org/10.3390/molecules23071513 - 22 Jun 2018

Cited by 8 | Viewed by 3284

Abstract

Cationic and non-peptide small molecules containing a total of six positive charges arranged on one side and a long aliphatic tail on the other have been synthesized and tested against Gram-positive and Gram-negative bacteria. The positive charges have been contributed by two aminophenol residues. These molecules have showed remarkable antimicrobial activity against Gram-positive bacteria including multidrug-resistant strains. Our structure–activity relationship studies demonstrated the importance of the length and flexibility of the hydrophobic tail for the antimicrobial activity. Importantly, these compounds are non-toxic to eukaryotic cells at the concentration affecting growth in bacteria, reflecting an acceptable margin of safety. The small size and easy synthetic accessibility of our molecules can be of interest for the further development of novel antimicrobials against Gram-positive bacterial pathogens, including multidrug-resistant strains. Full article

(This article belongs to the Special Issue Hit Generation and Verification for Novel Lead Compounds)

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19 pages, 1335 KiB

Open AccessFeature PaperArticle

Novel Semisynthetic Derivatives of Bile Acids as Effective Tyrosyl-DNA Phosphodiesterase 1 Inhibitors

by Oksana V. Salomatina, Irina I. Popadyuk, Alexandra L. Zakharenko, Olga D. Zakharova, Dmitriy S. Fadeev, Nina I. Komarova, Jóhannes Reynisson, H. John Arabshahi, Raina Chand, Konstantin P. Volcho, Nariman F. Salakhutdinov and Olga I. Lavrik

Molecules 2018, 23(3), 679; https://doi.org/10.3390/molecules23030679 - 17 Mar 2018

Cited by 24 | Viewed by 4887

Abstract

An Important task in the treatment of oncological and neurodegenerative diseases is the search for new inhibitors of DNA repair system enzymes. Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the DNA repair system enzymes involved in the removal of DNA damages caused by topoisomerase I inhibitors. Thus, reducing the activity of Tdp1 can increase the effectiveness of currently used anticancer drugs. We describe here a new class of semisynthetic small molecule Tdp1 inhibitors based on the bile acid scaffold that were originally identified by virtual screening. The influence of functional groups of bile acids (hydroxy and acetoxy groups in the steroid framework and amide fragment in the side chain) on inhibitory activity was investigated. In vitro studies demonstrate the ability of the semisynthetic derivatives to effectively inhibit Tdp1 with IC₅₀ up to 0.29 µM. Furthermore, an excellent fit is realized for the ligands when docked into the active site of the Tdp1 enzyme. Full article

(This article belongs to the Special Issue Hit Generation and Verification for Novel Lead Compounds)

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11 pages, 1733 KiB

Open AccessArticle

Regioselective Synthesis of Procyanidin B6, A 4-6-Condensed (+)-Catechin Dimer, by Intramolecular Condensation

by Yusuke Higashino, Taisuke Okamoto, Kazuki Mori, Takashi Kawasaki, Masahiro Hamada, Noriyuki Nakajima and Akiko Saito

Molecules 2018, 23(1), 205; https://doi.org/10.3390/molecules23010205 - 18 Jan 2018

Cited by 13 | Viewed by 4786

Abstract

Proanthocyanidins, also known as condensed tannins or oligomeric flavonoids, are found in many edible plants and exhibit interesting biological activities. Herein, we report a new, simple method for the stereoselective synthesis of procyanidin B6, a (+)-catechin-(4-6)-(+)-catechin dimer, by Lewis acid-catalyzed intramolecular condensation. The 5-O-t-butyldimethylsilyl (TBDMS) group of 5,7,3′4′-tetra-O-TBDMS-(+)-catechin was regioselectively removed using trifluoroacetic acid, leading to the “regio-controlled” synthesis of procyanidin B6. The 5-hydroxyl group of the 7,3′,4′-tri-O-TBDMS-(+)-catechin nucleophile and the 3-hydroxyl group of 5,7,3′,4′-tetra-O-benzylated-(+)-catechin electrophile were connected with an azelaic acid. The subsequent SnCl₄-catalyzed intramolecular condensation proceeded smoothly to give the 4-6-condensed catechin dimer. This is the first report on the complete regioselective synthesis of a 4-6-connected oligomer without modifying the 8-position. Full article

(This article belongs to the Special Issue Hit Generation and Verification for Novel Lead Compounds)

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14 pages, 2071 KiB

Open AccessArticle

Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents

by Ayesha Zafar, Lisa I. Pilkington, Natalie A. Haverkate, Michelle Van Rensburg, Euphemia Leung, Sisira Kumara, William A. Denny, David Barker, Ali Alsuraifi, Clare Hoskins and Jóhannes Reynisson

Molecules 2018, 23(1), 145; https://doi.org/10.3390/molecules23010145 - 11 Jan 2018

Cited by 16 | Viewed by 4665

Abstract

It is now established that the thieno[2,3-b]pyridines are a potent class of antiproliferatives. One of the main issues encountered for their clinical application is their low water solubility. In order to improve this, two strategies were pursued. First, a morpholine moiety was tethered to the molecular scaffold by substituting the sulphur atom with nitrogen, resulting in a 1H-pyrrolo[2,3-b]pyridine core structure. The water solubility was increased by three orders of magnitude, from 1.2 µg/mL (1-thieno[2,3-b]pyridine) to 1.3 mg/mL (3-pyrrolo[2,3-b]pyridine), however, it was only marginally active against cancer cells. The second strategy involved loading a very potent thieno[2,3-b]pyridine derivative (2) into a cholesteryl-poly(allylamine) polymer matrix for water solubilisation. Suppression of human pancreatic adenocarcinoma (BxPC-3) viability was observed to an IC₅₀ value of 0.5 μg/mL (1.30 μM) in conjunction with the polymer, which is a five-fold (×5) increase in potency as compared to the free drug alone, demonstrating the utility of this formulation approach. Full article

(This article belongs to the Special Issue Hit Generation and Verification for Novel Lead Compounds)

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6559 KiB

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GPCR Modulation of Thieno[2,3-b]pyridine Anti-Proliferative Agents

by Ayesha Zafar, Suat Sari, Euphemia Leung, Lisa I. Pilkington, Michelle Van Rensburg, David Barker and Jóhannes Reynisson

Molecules 2017, 22(12), 2254; https://doi.org/10.3390/molecules22122254 - 18 Dec 2017

Cited by 12 | Viewed by 4433

Abstract

A panel of docking scaffolds was developed for the known molecular targets of the anticancer agents, thieno[2,3-b]pyridines, in order to glean insight into their mechanism of action. The reported targets are the copper-trafficking antioxidant 1 protein, tyrosyl DNA phosphodiesterase 1, the colchicine binding site in tubulin, adenosine A2A receptor, and, finally, phospholipase C-δ1. According to the panel, the A2A receptor showed the strongest binding, inferring it to be the most plausible target, closely followed by tubulin. To investigate whether the thieno[2,3-b]pyridines modulate G protein-coupled receptors (GPCRs) other than A2A, a screen against 168 GPCRs was conducted. According to the results, ligand 1 modulates five receptors in the low µM region, four as an antagonist; CRL-RAMP3 (IC₅₀—11.9 µM), NPSR1B (IC₅₀—1.0 µM), PRLHR (IC₅₀—9.3 µM), and CXCR4 (IC₅₀—6.9 µM). Finally, one agonist, GPRR35, was found (EC₅₀ of 7.5 µM). Molecular modelling showed good binding to all of the receptors investigated; however, none of these surpass the A2A receptor. Furthermore, the newly-identified receptors are relatively modestly expressed in the cancer cell lines most affected by the thieno[2,3-b]pyridines, making them less likely to be the main targets of the mechanism of action for this compound class. Nevertheless, new modulators against GPCRs are of an interest as potential hits for further drug development. Full article

(This article belongs to the Special Issue Hit Generation and Verification for Novel Lead Compounds)

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Review

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19 pages, 6932 KiB

Open AccessReview

Development of an In Vitro Screening Platform for the Identification of Partial PPARγ Agonists as a Source for Antidiabetic Lead Compounds

by Lars Porskjær Christensen and Rime Bahij El-Houri

Molecules 2018, 23(10), 2431; https://doi.org/10.3390/molecules23102431 - 22 Sep 2018

Cited by 11 | Viewed by 4561

Abstract

Type 2 diabetes (T2D) is a metabolic disorder where insulin-sensitive tissues show reduced sensitivity towards insulin and a decreased glucose uptake (GU), which leads to hyperglycaemia. Peroxisome proliferator-activated receptor (PPAR)γ plays an important role in lipid and glucose homeostasis and is one of the targets in the discovery of drugs against T2D. Activation of PPARγ by agonists leads to a conformational change in the ligand-binding domain, a process that alters the transcription of several target genes involved in glucose and lipid metabolism. Depending on the ligands, they can induce different sets of genes that depends of their recruitment of coactivators. The activation of PPARγ by full agonists such as the thiazolidinediones leads to improved insulin sensitivity but also to severe side effects probably due to their behavior as full agonists. Partial PPARγ agonists are compounds with diminished agonist efficacy compared to full agonist that may exhibit the same antidiabetic effect as full agonists without inducing the same magnitude of side effects. In this review, we describe a screening platform for the identification of partial PPARγ agonists from plant extracts that could be promising lead compounds for the development of antidiabetic drugs. The screening platform includes a series of in vitro bioassays, such as GU in adipocytes, PPARγ-mediated transactivation, adipocyte differentiation and gene expression as well as in silico docking for partial PPARγ agonism. Full article

(This article belongs to the Special Issue Hit Generation and Verification for Novel Lead Compounds)

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