Integration of pharmacophore mapping and molecular docking in sequential virtual screening: towards the discovery of novel JAK2 inhibitors

摘要

An integrated virtual screening protocol by combining molecular docking and pharmacophore mapping was established to identify novel inhibitors of JAK2 from a commercial compound database. Twelve novel and structurally diverse hits were selected and subjected to in vitro biological tests, and three compounds (A5, A6 and A9) with remarkable JAK2 inhibitory activity were identified. Then, the obtained structures were further used as the template for a subsequent similarity search, leading to the identification of another two promising compounds (B2 and B4). Selectivity profiles of JAK subtype and in vitro anti-cancer activity of the promising compounds were studied, revealing the promising compound B2 was of interest for further study because of its JAK2 selective profile, novelty of skeleton and significantly anti-proliferative effect against cancer cells. Finally, binding patterns of the compounds A5 and B2 were explored to provide a deeper insight for further structural optimization.