Docking studies of Pakistani HCV NS3 helicase: a possible antiviral drug target.

Kaneez Fatima,Mohd Suhail,Shilu Mathew,Ashraf Ali,Ishtiaq Qadri,Ghazi Damanhouri,Esam Azhar,Shama Ahmad

doi:10.1371/journal.pone.0106339

Abstract

The nonstructural protein 3 (NS3) of hepatitis C virus (HCV) helicase is believed to be essential for viral replication and has become an attractive target for the development of antiviral drugs. The study of helicase is useful for elucidating its involvement in positive sense single-stranded RNA virus replication and to serve as templates for the design of novel antiviral drugs. In recent years, several models have been proposed on the conformational change leading to protein movement and RNA unwinding. Some compounds have been recently reported to inhibit the helicase and these include small molecules, RNA aptamers and antibodies. The current study is designed to help gain insights for the consideration of potential inhibitors for Pakistani HCV NS3 helicase protein. We have cloned, expressed and purified HCV NS3 helicase from Pakistani HCV serum samples and determined its 3D structure and employed it further in computational docking analysis to identify inhibitors against HCV genotype 3a (GT3a),including six antiviral key molecules such as quercetin, beta-carotene, resveratrol, catechins, lycopene and lutein. The conformation obtained after docking showed good hydrogen bond (HBond) interactions with best docking energy for quercetin and catechins followed by resveratrol and lutein. These anti-helicase key molecules will offer an alternative attraction to target the viral helicase, due to the current limitation with the interferon resistance treatment and presences of high rate of resistance in anti-protease inhibitor classes.

Highlights

Hepatitis C virus (HCV) is one of the major causative agent of chronic hepatitis which leads to liver cirrhosis, hepato cellular carcinoma, and liver failure and the most significant cause for liver transplantation [1,2]
HCV RNA genome encodes a single open reading frame that is translated into 3,000 amino acids (AA) poly protein and cleaved into 10 mature proteins
HCV genome translated into 4 structural (Core, E1 E2 and p7), and 6 important nonstructural (NS) proteins: NS2, nonstructural protein 3 (NS3), NS4A, NS4B, NS5A, and NS5B [5], which coordinate the intracellular processes of the viral life cycle

Summary

Introduction

Hepatitis C virus (HCV) is one of the major causative agent of chronic hepatitis which leads to liver cirrhosis, hepato cellular carcinoma, and liver failure and the most significant cause for liver transplantation [1,2]. Among all HCV proteins, NS3/NS4A serine protease and helicase are effective drug targets to develop anti-HCV agents [7]. Two NS3 protease inhibitors have been approved as a standard care for HCV GT1 affected patients by providing treatment with triple therapy Imminent treatments for individuals infected by HCV will likely involve combinations of compounds that inhibit multiple viral targets. We cloned, purified HCV helicase, determined its 3D structure and docked with different available inhibitors chosen from the family of bioflavonoids. We determined active inhibitors against genotype 3a (GT3a) NS3 helicase strain to pave a way to treat HCV patients in Pakistan

Methodology and principal findings

Findings

Result and Discussion