3D-QSAR, Molecular Docking and Molecular Dynamics Simulations of 3-Phenylsulfonylaminopyridine Derivatives as Novel PI3Kα Inhibitors

The p110 alpha, catalytic subunit of PI3K alpha, was the primary phosphoinositide 3-kinases (PI3Ks) isoform involved in oncogenic RTK signaling and tumorigenesis. In this study, the three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics simulation were employed to study the binding mode between 3-phenylsulfonylaminopyridine derivatives and PI3K alpha. The stable and reliable 3D-QSAR models were constructed based on the application of the comparative molecular field analysis (CoMFA) model (q(2) = 0.704, r(2) = 0.994) and comparative molecular similarity index analysis (CoMSIA) model (q(2) = 0.804, r(2) = 0.996). The contour maps illustrated relationship between structure and biological activity. The conformation obtained after MD simulation was more stable than the docked conformation. MD simulation was performed in a more realistic environment, and was much closer to physiological conditions. As a result, five novel PI3K alpha inhibitors were designed with better biological activity than the template compound 8.