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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 (3 papers)

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Research

Open AccessArticle Regioselective Synthesis of Procyanidin B6, A 4-6-Condensed (+)-Catechin Dimer, by Intramolecular Condensation
Molecules 2018, 23(1), 205; doi:10.3390/molecules23010205
Received: 9 January 2018 / Revised: 15 January 2018 / Accepted: 16 January 2018 / Published: 18 January 2018
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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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Open AccessArticle Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents
Molecules 2018, 23(1), 145; doi:10.3390/molecules23010145
Received: 18 December 2017 / Revised: 3 January 2018 / Accepted: 8 January 2018 / Published: 11 January 2018
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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Open AccessArticle GPCR Modulation of Thieno[2,3-b]pyridine Anti-Proliferative Agents
Molecules 2017, 22(12), 2254; doi:10.3390/molecules22122254
Received: 30 November 2017 / Revised: 11 December 2017 / Accepted: 15 December 2017 / Published: 18 December 2017
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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