Virtual screening and bioassay study of novel inhibitors for dengue virus mRNA cap (nucleoside-2′O)-methyltransferase

详细信息    查看全文

• 作者：Victor B. Luzhkov ; Barbara Selisko ; Anneli Nordqvist ; Fré ; dé ; ric Peyrane ; Etienne Decroly ; Karine Alvarez ; Anders Karlen ; Bruno Canard ; Johan Å ; qvist
• 关键词：Flavivirus methyltransferase inhibitor ; Drug design ; Virtual screening ; Docking
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2007
• 出版时间：15 December 2007
• 年：2007
• 卷：15
• 期：24
• 页码：7795-7802
• 全文大小：879 K

文摘

We report high-throughput structure-based virtual screening of putative Flavivirus 2′-O-methyltransferase inhibitors together with results from subsequent bioassay tests of selected compounds. Potential inhibitors for the S-adenosylmethionine binding site were explored using 2D similarity searching, pharmacophore filtering and docking. The inhibitory activities of 15 top-ranking compounds from the docking calculations were tested on a recombinant methyltransferase with the RNA substrate ^7MeGpppAC₅. Local and global docking simulations were combined to estimate the ligand selectivity for the target site. The results of the combined computational and experimental screening identified a novel inhibitor, with a previously unknown scaffold, that has an IC₅₀ value of 60 μM.