Identification of Potential Selective PAK4 Inhibitors Through Shape and Protein Conformation Ensemble Screening and Electrostatic-Surface-Matching Optimization.

ABSTRACT: P21-activated kinase 4 (PAK4) plays a crucial role in the proliferation and metastasis of various cancers. However, developing selective PAK4 inhibitors remains challenging due to the high homology within the PAK family. Therefore, developing highly selective PAK4 inhibitors is critical to overcoming the limitations of existing inhibitors. We analyzed the structural differences in the binding pockets of PAK1 and PAK4 by combining cross-docking and molecular dynamics simulations to identify key binding regions and unique structural features of PAK4. We then performed screening using shape and protein conformation ensembles, followed by a re-evaluation of the docking results with deep-learning-driven GNINA to identify the candidate molecule, STOCK7S-56165. Based on this, we applied a fragmen

SUBMITTER: Zhang X 

PROVIDER: S-EPMC11764389 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature