Water-Based Pharmacophore Modeling in Kinase Inhibitor Design: A Case Study on Fyn and Lyn Protein Kinases.

ABSTRACT: Water-based pharmacophore modeling is an emerging approach in inhibitor design that leverages the dynamics of explicit water molecules within ligand-free, water-filled binding sites to derive 3D pharmacophores for virtual screening. In this study, we assess the potential of this strategy through a case study targeting the ATP binding sites of Fyn and Lyn protein kinases─members of the Src family that have been less explored in anticancer drug discovery compared to other family members. Molecular dynamics simulations of multiple kinase structures were used to generate and validate several water-derived pharmacophores, which were subsequently employed to screen chemically diverse libraries of compounds. Two active compounds were identified in biochemical assays: a flavonoid-like molecule wit

SUBMITTER: Ljubic M 

PROVIDER: S-EPMC12458683 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature