Structural Basis For Tailor-Made Selective Pi3k Alpha/Beta Inhibitors: A Computational Perspective

PI3K alpha and beta 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 alpha and beta. 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 PI3K alpha and PI3K beta inhibitors. It was found that the VAL851 of PI3K alpha and VAL848 of PI3K beta remarkably affected their selectivity by forming hydrogen bonds with different molecular scaffolds. Moreover, a diverse amino acid, GLN859 of PI3K alpha and ASP856 of PI3K beta greatly contributed to distinguishing the inhibitory selectivity between PI3K alpha and beta. Of note, PI3K beta seemed to form more water bridges with the surrounding water molecules. Collectively, these data shed light in depicting the PI3K alpha/beta selective mechanisms, which guided the future strategy for a rational design of selective inhibitors towards PI3K alpha/beta.