title: Molecular models of NS3 protease variants of the Hepatitis C virus.
abstract: BACKGROUND
  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. 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  This 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.
authors.affiliation: Department of Physics, IBILCE/UNESP, São José do Rio Preto, São Paulo, Brazil. nelsonj@webmail.ibilce.unesp.br
authors.forename: Nelson J F
authors.initials: NJ
authors.lastname: da Silveira
authors.forename: Helen A
authors.initials: HA
authors.lastname: Arcuri
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Bonalumi
authors.forename: Fátima P
authors.initials: FP
authors.lastname: de Souza
authors.forename: Isabel M V G C
authors.initials: IM
authors.lastname: Mello
authors.forename: Paula
authors.initials: P
authors.lastname: Rahal
authors.forename: João R R
authors.initials: JR
authors.lastname: Pinho
authors.forename: Walter F
authors.initials: WF
authors.lastname: de Azevedo
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D002918:Chymotrypsin / Q000737:chemistry; D019295:Computational Biology / Q000379:methods*; D018360:Crystallography, X-Ray; D030541:Databases, Genetic; D030562:Databases, Protein; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D014644:Genetic Variation; D016174:Hepacivirus / Q000235:genetics*; D020407:Internet; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D020365:RNA Helicases / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D002918:Chymotrypsin; D004791:Enzyme Inhibitors; D008024:Ligands; D010455:Peptides; D020365:RNA Helicases; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases