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Special Issue "Hit Generation and Verification for Novel Lead Compounds"

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

Deadline for manuscript submissions: 30 June 2018

Special Issue Editor

Guest Editor
Dr. Jóhannes Reynisson FRSC

School of Chemical Sciences, University of Auckland, New Zealand
Website | E-Mail
Interests: virtual screening; molecular modelling; known drug space; density functional theory

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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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 (4 papers)

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Research

Open AccessFeature PaperArticle Novel Semisynthetic Derivatives of Bile Acids as Effective Tyrosyl-DNA Phosphodiesterase 1 Inhibitors
Molecules 2018, 23(3), 679; https://doi.org/10.3390/molecules23030679
Received: 2 March 2018 / Revised: 14 March 2018 / Accepted: 16 March 2018 / Published: 17 March 2018
PDF Full-text (1335 KB) | HTML Full-text | XML Full-text | Supplementary Files
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
[...] Read more.
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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Graphical abstract

Open AccessArticle Regioselective Synthesis of Procyanidin B6, A 4-6-Condensed (+)-Catechin Dimer, by Intramolecular Condensation
Molecules 2018, 23(1), 205; https://doi.org/10.3390/molecules23010205
Received: 9 January 2018 / Revised: 15 January 2018 / Accepted: 16 January 2018 / Published: 18 January 2018
PDF Full-text (1733 KB) | HTML Full-text | XML Full-text
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
[...] Read more.
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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Graphical abstract

Open AccessArticle Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents
Molecules 2018, 23(1), 145; https://doi.org/10.3390/molecules23010145
Received: 18 December 2017 / Revised: 3 January 2018 / Accepted: 8 January 2018 / Published: 11 January 2018
Cited by 1 | PDF Full-text (2071 KB) | HTML Full-text | XML Full-text | Supplementary Files
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
[...] Read more.
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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Graphical abstract

Open AccessArticle GPCR Modulation of Thieno[2,3-b]pyridine Anti-Proliferative Agents
Molecules 2017, 22(12), 2254; https://doi.org/10.3390/molecules22122254
Received: 30 November 2017 / Revised: 11 December 2017 / Accepted: 15 December 2017 / Published: 18 December 2017
Cited by 1 | PDF Full-text (6559 KB) | HTML Full-text | XML Full-text | Supplementary Files
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
[...] Read more.
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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Graphical abstract

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Development of an in vitro screening platform for the identification of partial PPARγ agonists as a source for antidiabetic lead compounds
Authors: Lars Porskjær Christensen 1,* and Rime Bahji El-Houri 2
Affiliations: 1 Department of Chemistry and Bioscience, Faculty of Engineering and Science, Aalborg University, Fredrik Bajers Vej 7H, 9220 Aalborg Ø, Denmark; lpc@adm.aau.dk
2 Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark; rbeh@kbm.sdu.dk
* Correspondence: lpc@adm.aau.dk; Tel.: +45-277-874-94
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 altering 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 PPAR

Title: A high-content zebrafish chemical screen reveals new enhancers of Fgf/Ras/Mapk signaling as probes for zebrafish heart development.
Author: Michael Wai Kok Tsang; tsang@pitt.edu
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 embryonic development.  We screened over 10,000 compounds from the TIMTEC Diversity Set and identified five structurally distinct classes of molecules that enhanced Fgf/Ras/Mapk signaling in the developing larvae. We chose three agents, PT6994, PT20101, and PT11282, for confirmatory and functional studies based on potency, repeatability with authentic material, favorable toxicity profiles, and evidence of structure-activity relationships.  All three compounds induced expression of Fgf target genes during zebrafish embryonic development. Moreover, embryos treated with these compounds converted neighboring endothelial progenitors into cardiac progenitors that translated into increased cardiomyocyte numbers. Interestingly, PT6994 hyperactivated Fgf signaling in the absence of Erk phosphorylation, suggesting a molecular mechanism of action downstream of Mapks. We posit that the PT6994 pharmacophore could become a unique chemical probe to uncover novel mechanisms of Fgf/Ras/Mapk signaling during heart development.

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