Discovery of octahydropyrrolo [3,2‐b] pyridin derivative as a highly selective Type I inhibitor of FGFR3 over VEGFR2 by high‐throughput virtual screening

Abstract Although the aberrant activity of fibroblast growth factor receptor 3 (FGFR3) is implicated in various cancers, the reported kinase inhibitors of FGFR3 tend to cause side effects resulting from the inhibitory activity on vascular endothelial growth factor receptor 2 (VEGFR2). Therefore, it is necessary to find a novel high‐selective inhibitor of FGFR3 over VEGFR2 from the small‐molecule compound database. In this study, integrated virtual screening protocols were established to screen for selective inhibitors of FGFR3 over VEGFR2 in Drugbank and Asinex databases by combining three‐dimensional pharmacophore model, molecular docking, molecular dynamics (MD) simulation, and molecular mechanics Poisson–Boltzmann surface area (MMPBSA) calculations. Finally, it is found that Asinex‐5082, as an octahydropyrrolo[3,2‐b] pyridin derivative, has larger binding free energy with FGFR3 (−39.3 kcal/mol) than reference drug Erdafitinib (−29.9 kcal/mol), while cannot bind with VEGFR2, resulting in considerable inhibitory selectivity. This is because Asinex‐5082, unlike Erdafitinib, has not m ‐dimethoxybenzene with large steric hindrance, thus can enter the larger ATP‐binding pocket of FGFR3 with DFG‐in conformation to form hydrophobic interaction with residues Met529, Ile539, and Tyr557 as well as hydrogen bond with Ala558. On the other hand, due to the fact that the benzodioxane and N‐heterocyclic rings are connected by carbonyl (C=O), Asinex‐5082 cannot rotate freely so as to enter the smaller ATP binding pocket of VEGFR2 on the DFG‐out conformation. The lead molecule Asinex‐5082 may facilitate the rational design and development of novel selective inhibitors of FGFR3 over VEGFR2 as anticancer drugs.