Computational medicinal chemistry applications to target Asian-prevalent strain of hepatitis C virus

Hepatitis C Virus (HCV), affecting millions of people worldwide, is the leading cause of liver disorder, cirrhosis, and hepatocellular carcinoma. HCV is genetically diverse having eight genotypes and several subtypes predominant in different regions of the globe. The HCV NS3/4A protease is a primary...

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Bibliographic Details
Published in:	RSC advances Vol. 13; no. 43; pp. 352 - 37
Main Authors:	Hussain, Rashid, Haider, Zulkarnain, Khalid, Hira, Fatmi, M. Qaiser, Carradori, Simone, Cataldi, Amelia, Zara, Susi
Format:	Journal Article
Language:	English
Published:	England Royal Society of Chemistry 11-10-2023 The Royal Society of Chemistry
Subjects:	Chemistry Fibroblasts Hepatitis C Molecular dynamics Protease Protease inhibitors Software Surface plasmon resonance Zinc
Online Access:	Get full text
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Summary:	Hepatitis C Virus (HCV), affecting millions of people worldwide, is the leading cause of liver disorder, cirrhosis, and hepatocellular carcinoma. HCV is genetically diverse having eight genotypes and several subtypes predominant in different regions of the globe. The HCV NS3/4A protease is a primary therapeutic target for HCV with various FDA-approved antivirals and several clinical developments. However, available protease inhibitors (PIs) have lower potency against HCV genotype 3 (GT3), prevalent in South Asia. In this study, the incumbent computational tools were utilized to understand and explore interactions of the HCV GT3 receptor with the potential inhibitors after the virtual screening of one million compounds retrieved from the ZINC database. The molecular dynamics, pharmacological studies, and experimental studies uncovered the potential PIs as ZINC000224449889, ZINC000224374291, and ZINC000224374456 and the derivative of ZINC000224374456 from the ZINC library. The study revealed that these top-hit compounds exhibited good binding and better pharmacokinetics properties that might be considered the most promising compound against HCV GT3 protease. Viability test, on primary healthy Human Gingival Fibroblasts (HGFs) and cancerous AGS cell line, was also carried out to assess their safety profile after administration. In addition, Surface Plasmon Resonance (SPR) was also performed for the determination of affinity and kinetics of synthesized compounds with target proteins. Hepatitis C Virus (HCV), affecting millions of people worldwide, is the leading cause of liver disorder, cirrhosis, and hepatocellular carcinoma.
Bibliography:	https://doi.org/10.1039/d3ra04622b Electronic supplementary information (ESI) available. See DOI ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2046-2069 2046-2069
DOI:	10.1039/d3ra04622b