Novel inhibitors of dengue virus methyltransferase: discovery by in vitro-driven virtual screening on a desktop computer grid.
Dengue fever is a viral disease that affects 50-100 million people annually and is one of the most important emerging infectious diseases in many areas of the world. Currently, neither specific drugs nor vaccines are available. Here, we report on the discovery of new inhibitors of the viral NS5 RNA methyltransferase, a promising flavivirus drug target. We have used a multistage molecular docking approach to screen a library of more than 5 million commercially available compounds against the two binding sites of this enzyme. In 263 compounds chosen for experimental verification, we found 10 inhibitors with IC(50) values of <100 microM, of which four exhibited IC(50) values of <10 microM in in vitro assays. The initial hit list also contained 25 nonspecific aggregators. We discuss why this likely occurred for this particular target. We also describe our attempts to use aggregation prediction to further guide the study, following this finding.
Podvinec
Michael
M
Swiss Institute of Bioinformatics and Biozentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
Lim
Siew Pheng
SP
Schmidt
Tobias
T
Scarsi
Marco
M
Wen
Daying
D
Sonntag
Louis-Sebastian
LS
Sanschagrin
Paul
P
Shenkin
Peter S
PS
Schwede
Torsten
T
D001665:Binding Sites; D003201:Computers; D016208:Databases, Factual; D003716:Dengue Virus / Q000201:enzymology*; D055808:Drug Discovery; D008024:Ligands; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011485:Protein Binding; D013329:Structure-Activity Relationship
D008024:Ligands; D004364:Pharmaceutical Preparations; D008780:Methyltransferases