Structure function analysis of west nile virus RNA dependent RNA polymerase: molecular model and implications for drug design.
West Nile virus (WNV) is a mosquito-borne disease that emerged in North America. In 2002 it caused the largest arboviral meningoencephalitis outbreak ever recorded in the US and Canada. The key enzyme responsible for the replication of the virus is the RNA-dependent RNA polymerase (RdRp) enzyme represented by nonstructural protein NS5 in WNV. To understand the structural basis and enzymatic activity of WNV RdRp as well as potential drug susceptibility, we have built a homology model of WNV NS5 RdRp based on a combination of motif search, fold recognition and sequence alignments orchestrated by 3D-jury system. We have located conserved sequence motifs shared by all RdRps and described the potential functional role of these motifs and specific residues in the polymerization and in the recognition of potential inhibitors. Virtual docking of several substrates and inhibitors in our WNV RdRp model shows that a non-nucleoside inhibitor such as 2'-methyl-ribofuranosyl-guanosine triphosphate has a higher binding energy indicated by a low free energy obtained upon binding. These results provide a preliminary basis for the development of anti-WNV agents based on RNA dependant RNA polymerase inhibition.
Azzi
Arezki
A
Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (CHUQ), 2705 Boul Laurier, Quebec, Canada.
Lin
Sheng-Xiang
SX
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry*; D015195:Drug Design; D008958:Models, Molecular; D008969:Molecular Sequence Data; D012324:RNA-Dependent RNA Polymerase / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014902:West Nile virus / Q000201:enzymology*
D000998:Antiviral Agents; D012324:RNA-Dependent RNA Polymerase