Discovery of small molecule inhibitors against the NS3/4A serine protease of Hepatitis C virus genotype 3 via highthroughput virtual screening and in vitro evaluations
https://doi.org/10.47665/tb.37.3.609
- Author:
Sakhor, W.
1
;
Teoh, T.C.
2
;
Yusof, R.
1
;
Lim, S.K.
3
;
Razif, M.F.M.
1
Author Information
1. Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
2. Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Malaya, 50603 Kuala Lumpur, Malaysia
- Publication Type:Journal Article
- From:Tropical Biomedicine
2020;37(No.3):609-625
- CountryMalaysia
- Language:English
-
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 106.7µM and EC50 of 25.8µM, respectively. Thus, compound A may be developed as a potent, low molecular weight drug against the HCV NS3/4A serine protease of GT3.
- Full text:8.2020my1149.pdf
