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

Using a combination of virtual screening and bioassay activity testing, a novel inhibitor of a flavivirus mRNA capping methyltransferase has been identified. 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 7MeGpppAC 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 μM.