Discovery of small molecule inhibitors against the NS3/4A serine protease of Hepatitis C virus genotype 3 via high-throughput virtual screening and in vitro evaluations

Sakhor, W. and Teoh, T. C. and Yusof, R. and Lim, S. K. and Razif, M. F. M. (2020) Discovery of small molecule inhibitors against the NS3/4A serine protease of Hepatitis C virus genotype 3 via high-throughput virtual screening and in vitro evaluations. Tropical Biomedicine, 37 (3). pp. 609-625. ISSN 0127-5720,

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Abstract

The hepatitis C virus (HCV) consists of eight genotypes and 90 subtypes, with genotype (GT) 3 being the second most common globally and is linked to higher incidences of steatosis and rapid development of fibrosis and cirrhosis. The NS3/4A serine protease, a heterodimer complex of two HCV non-structural proteins, is an effective target for pharmaceutical intervention due to its essential roles in processing HCV polyproteins and inhibiting innate immunity. This study combines structure-based virtual screening (SBVS) of predefined compound libraries, pharmacokinetic prediction (ADME/T) and in vitro evaluation to identify potential low molecular weight (<500 Dalton) inhibitors of the NS3/4A serine protease (GT3). In silico screening of ZINC and PubChem libraries yielded five selected compounds as potential candidates. Dose-dependent inhibition of the NS3/4A serine protease and HCV replication in HuH-7.5 cells revealed that compound A (PubChem ID No. 16672637) exhibited inhibition towards HCV GT3 with an IC50 of 106.7 mu M and BC EC50 of 25.8 mu M, respectively. Thus, compound A may be developed as a potent, low molecular weight drug against the HCV NS3/4A serine protease of GT3.

Item Type: Article
Funders: Ministry of Education Malaysia-Transdisciplinary Research Grants Scheme [Grant No: TR001B-2014B], Universiti Malaya [Grant No: PG238-2016A]
Uncontrolled Keywords: Antiviral Agents; Cell Line; Drug Evaluation, Preclinical; Hepacivirus; Humans; Molecular Docking Simulation; Molecular Structure; Protease Inhibitors; Protein Structure, Tertiary; Serine Proteases; Viral Nonstructural Proteins
Subjects: Q Science > QH Natural history > QH301 Biology
R Medicine > R Medicine (General)
R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Medicine > Department of Molecular Medicine
Faculty of Science > Institute of Biological Sciences
Faculty of Pharmacy > Department of Pharmaceutical Chemistry
Depositing User: Ms Zaharah Ramly
Date Deposited: 28 Oct 2024 07:38
Last Modified: 28 Oct 2024 07:38
URI: http://eprints.um.edu.my/id/eprint/36458

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