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
Document Type
Article
Publication Date
9-1-2020
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.
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
Divisions
molecular,InstituteofBiologicalSciences,pharchemistry
Funders
Ministry of Education Malaysia-Transdisciplinary Research Grants Scheme [Grant No: TR001B-2014B],Universiti Malaya [Grant No: PG238-2016A]
Publication Title
Tropical Biomedicine
Volume
37
Issue
3
Publisher
Malaysian Society for Parasitology
Publisher Location
C/O INST MEDICAL REEARCH, JALAN PAHANG, KUALA LUMPUR, 50588, MALAYSIA