Structural basis for tailor-made selective PI3K α/β inhibitors: a computational perspective

Abstract

PI3K α and β are Class IA PI3K isoforms that share a highly homologous ATP binding site, differing only in a few residues around the binding site. They are ubiquitously expressed in various organs and play many different roles in terms of mutations in carcinomas and signaling in tumor growth. Their pan-inhibitors should theoretically be effective against cancers by offering a potentially broader spectrum of activity, however, clinical development of most panPI3K inhibitors has discontinued probably owing to the problematic toxicities. Therefore, it is crucial to clarify the structural basis of the selective inhibition mechanism towards PI3K α and β. Towards this end, comprehensive computational approaches including molecular docking, molecular dynamics simulations, mutagenesis, and DFT technologies were applied to reveal the different interaction modes between highly selective PI3Kα and PI3Kβ inhibitors. It was found that the VAL851 of PI3Kα and VAL848 of PI3Kβ remarkably affected their selectivity by forming hydrogen bonds with different molecular scaffolds. Moreover, a diverse amino acid, GLN859 of PI3K α and ASP856 of PI3Kβ greatly contributed to distinguishing the inhibitory selectivity between PI3Kα and β. Of note, PI3Kβ seemed to form more water bridges with the surrounding water molecules. Collectively, these data shed light in depicting the PI3Kα/β selective mechanisms, which guided the future strategy for a rational design of selective inhibitors towards PI3Kα/β.