Combining pharmacophore, docking and substructure search approaches to identify and optimize novel B-RafV600E inhibitors

Abstract In this study for searching novel B-Raf V600E inhibitors, pharmacophore-based virtual screening identified 1 as a hit bearing 5-benzylidene-2-thioxodihydropyrimidine-4,6(1 H ,5 H )-dione. Based on 1 , scaffold hopping inspired by molecular docking discovered 5-(furan-2-ylmethylene)-2-thioxodihydropyrimidine-4,6(1 H ,5 H )-dione as a new and better scaffold. Substructure search with the new scaffold identified 28 active compounds, among which 12 compounds (42.9%) showed IC 50 less than 1 μM. Especially, compound 3o , which is 10-fold more potent than the hit 1 , is a potent inhibitor comparable to that of the marketed drug vemurafenib.