Novel Inhibitors of Dengue Virus Methyltransferase: Discovery by in Vitro-Driven Virtual Screening on a Desktop Computer Grid

作者：Podvinec Michael; Lim Siew Pheng; Schmidt Tobias; Scarsi Marco; Wen Daying; Sonntag Louis Sebastian; Sanschagrin Paul; Shenkin Peter S; Schwede Torsten^*

来源：Journal of Medicinal Chemistry, 2010, 53(4): 1483-1495.

DOI：10.1021/jm900776m

Dengue fever is a viral disease that affects 50-100 million people annually and is one of the most important emerging Infectious diseases ill many areas of the world. Currently, neither specific drugs nor vaccines are available. Here, we report oil 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, WC found 10 inhibitors with IC(50) values of < 100 mu M, of which four exhibited IC(50) values of < 10 mu M in in vitro assays. The initial lilt 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.

• 出版日期2010-2-25