Virtual screening and bioassay study of novel inhibitors for dengue virus mRNA cap (nucleoside-2'O)-methyltransferase.
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 (7Me)GpppAC(5). 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 IC(50) value of 60 microM.
Luzhkov
Victor B
VB
Department of Cell and Molecular Biology, Uppsala University, BMC, Box 596, S-751 24 Uppsala, Sweden.
Selisko
Barbara
B
Nordqvist
Anneli
A
Peyrane
Frédéric
F
Decroly
Etienne
E
Alvarez
Karine
K
Karlen
Anders
A
Canard
Bruno
B
Qvist
Johan
J
D001665:Binding Sites; D001681:Biological Assay; D003716:Dengue Virus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008024:Ligands; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008958:Models, Molecular; D015394:Molecular Structure; D012333:RNA, Messenger / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019065:Virus Assembly / Q000187:drug effects
D004791:Enzyme Inhibitors; D008024:Ligands; D012333:RNA, Messenger; D011994:Recombinant Proteins; D008780:Methyltransferases; C032117:cap I RNA (nucleoside-2'-)methyltransferase