Structure-based virtual screening, synthesis and SAR of novel inhibitors of hepatitis C virus NS5B polymerase.

Bioorganic & Medicinal Chemistry
Tanaji T TaleleNeerja Kaushik-Basu

Abstract

Hepatitis C virus (HCV) NS5B polymerase is a key target for the development of therapeutic agents aimed at the treatment of HCV infections. Here we report on the identification of novel allosteric inhibitors of HCV NS5B through a combination of structure-based virtual screening, synthesis and structure-activity relationship (SAR) optimization approach. Virtual screening of 260,000 compounds from the ChemBridge database against the tetracyclic indole inhibitor binding pocket of NS5B (allosteric pocket-1, AP-1), sequentially down-sized the library by 4 orders of magnitude to yield 23 candidates. In vitro evaluation of the NS5B inhibitory activity of the in-silico selected compounds resulted in 17% hit rate, identifying two novel chemotypes. Of these, compound 3, bearing the rhodanine scaffold, proved amenable for productive SAR exploration and synthetic modification. As a result, 25 derivatives that exhibited IC₅₀ values ranging from 7.7 to 68.0 μM were developed. Docking analysis of lead compound 28 within the tetracyclic indole- and benzylidene-binding allosteric pockets (AP-1 and AP-3, respectively) of NS5B revealed topological similarities between these two pockets. Compound 28, a novel rhodanine analog with NS5B inhibitory p...Continue Reading

References

Jan 28, 2003·Drug Discovery Today·Paul D Lyne
Jan 22, 2008·Nucleic Acids Research·Neerja Kaushik-BasuFrançois Noël

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Citations

Oct 29, 2013·European Journal of Medicinal Chemistry·Ilkay KüçükgüzelNeerja Kaushik-Basu
Jun 29, 2011·Future Medicinal Chemistry·Maria Letizia BarrecaVioletta Cecchetti
Feb 15, 2016·European Journal of Medicinal Chemistry·Talita de A FernandesPaulo R R Costa
Sep 27, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Nguyen Tien CongPing-Chung Kuo
May 23, 2012·Expert Opinion on Drug Discovery·Tihomir Tomašić, Lucija Peterlin Mašič
Nov 7, 2012·European Journal of Medicinal Chemistry·Andriy G GolubNeerja Kaushik-Basu
Sep 26, 2013·Drug Discovery Today. Technologies
Feb 7, 2017·Expert Opinion on Drug Discovery·Aravindhan Ganesan, Khaled Barakat
Oct 12, 2017·Expert Opinion on Drug Discovery·Danylo KaminskyyRoman Lesyk
Apr 4, 2019·Artificial Cells, Nanomedicine, and Biotechnology·Seyyed Mojtaba MousaviAli Mohammad Amani
May 26, 2020·Journal of Computational Chemistry·Aijaz Ahmad MalikChanin Nantasenamat
Dec 7, 2018·Medicinal Research Reviews·Muhammad Usman AshrafSafee Ullah Chaudhary
Aug 14, 2020·Journal of Agricultural and Food Chemistry·Tao ChenGuang-Fu Yang
Oct 9, 2021·Journal of Computer-aided Molecular Design·Aijaz Ahmad MalikWatshara Shoombuatong

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