title: Novel inhibitors of dengue virus methyltransferase: discovery by in vitro-driven virtual screening on a desktop computer grid.
abstract: 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.
authors.affiliation: Swiss Institute of Bioinformatics and Biozentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Podvinec
authors.forename: Siew Pheng
authors.initials: SP
authors.lastname: Lim
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmidt
authors.forename: Marco
authors.initials: M
authors.lastname: Scarsi
authors.forename: Daying
authors.initials: D
authors.lastname: Wen
authors.forename: Louis-Sebastian
authors.initials: LS
authors.lastname: Sonntag
authors.forename: Paul
authors.initials: P
authors.lastname: Sanschagrin
authors.forename: Peter S
authors.initials: PS
authors.lastname: Shenkin
authors.forename: Torsten
authors.initials: T
authors.lastname: Schwede
mesh_terms: 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
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D008780:Methyltransferases