Molecular models of NS3 protease variants of the Hepatitis C virus

Nelson Jf Da Silveira,Isabel Mvgc Mello,João Rr Pinho,Paula Rahal,Fátima P De Souza,Carlos E Bonalumi,Helen A Arcuri,Walter F De Azevedo

doi:10.1186/1472-6807-5-1

Abstract

BackgroundHepatitis C virus (HCV) currently infects approximately three percent of the world population. In view of the lack of vaccines against HCV, there is an urgent need for an efficient treatment of the disease by an effective antiviral drug. Rational drug design has not been the primary way for discovering major therapeutics. Nevertheless, there are reports of success in the development of inhibitor using a structure-based approach. One of the possible targets for drug development against HCV is the NS3 protease variants. Based on the three-dimensional structure of these variants we expect to identify new NS3 protease inhibitors. In order to speed up the modeling process all NS3 protease variant models were generated in a Beowulf cluster. The potential of the structural bioinformatics for development of new antiviral drugs is discussed.ResultsThe atomic coordinates of crystallographic structure 1CU1 and 1DY9 were used as starting model for modeling of the NS3 protease variant structures. The NS3 protease variant structures are composed of six subdomains, which occur in sequence along the polypeptide chain. The protease domain exhibits the dual beta-barrel fold that is common among members of the chymotrypsin serine protease family. The helicase domain contains two structurally related beta-alpha-beta subdomains and a third subdomain of seven helices and three short beta strands. The latter domain is usually referred to as the helicase alpha-helical subdomain. The rmsd value of bond lengths and bond angles, the average G-factor and Verify 3D values are presented for NS3 protease variant structures.ConclusionsThis project increases the certainty that homology modeling is an useful tool in structural biology and that it can be very valuable in annotating genome sequence information and contributing to structural and functional genomics from virus. The structural models will be used to guide future efforts in the structure-based drug design of a new generation of NS3 protease variants inhibitors. All models in the database are publicly accessible via our interactive website, providing us with large amount of structural models for use in protein-ligand docking analysis.

Highlights

Hepatitis C virus (HCV) currently infects approximately three percent of the world population
We modeled the structure of variants of nonstructural protein 3 (NS3) protease variants available in the National Center for Biotchnology Information (Genbank), using structural bioinformatics tools
Quality of the models The atomic coordinates of crystallographic structure 1CU1 solved to resolution of the 2.5 Å were used as starting model for modeling of the NS3 protease variant structures, and the structure of NS3 complexed with an inhibitor (PDB access code: 1DY9) was used to generate homology models for docking studies

Summary

Introduction

Hepatitis C virus (HCV) currently infects approximately three percent of the world population. In view of the lack of vaccines against HCV, there is an urgent need for an efficient treatment of the disease by an effective antiviral drug. Physical prediction methods are based on interactions between atoms and include molecular dynamics and energy minimization [12], whereas the empirical methods depend on the protein structures that have been already determined by experiment. In view of the lack of vaccines against HCV, there is an urgent need for a treatment of the disease by an effective antiviral drug. This necessity has boosted research on the structural biology of HCV with the primary focus being to identify possible targets for pharmaceutical intervention [3]

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