Structure-based virtual screening and ADME/T-based profiling for low molecular weight chemical starting points as p21-activated kinase 4 inhibitors

摘要

A structure-based virtual screening approach to targeting p21-activated kinase 4 (PAK4) was performed to identify good chemical starting points for medicinal chemistry. A pre-filtrated database was screened against two designed PAK4 pharmacophores, and the pharmacophore search hits were docked into a PAK4 crystal structure. Twenty-seven compounds were then selected for in vitro PAK4 inhibition assay, and results showed three compounds exhibiting a micro-molar IC50 in a dose-response assay. Interactive modes of the three compounds were studied and showed good binding modes in the PAK4 active site. Calculated ADME/T properties of the three hits were also analyzed and showed good drug-like properties. The results of in vitro PAK4 inhibition assay, interactive mode study and ADME/T prediction revealed that the three compounds have potential PAK4 inhibitory activities and can be further optimized and developed as lead compounds.