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

• Main Authors: Sakhor, W., Teoh, T. C., Yusof, R., Lim, S. K., Razif, M. F. M.
• Format: Article
• Published: Malaysian Society for Parasitology 2020
• Subjects: QH301 Biology; R Medicine (General); RS Pharmacy and materia medica
• Online Access: http://eprints.um.edu.my/36458/
• Institution: Universiti Malaya

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.