Docking studies on isoform-specific inhibition of phosphoinositide-3-kinases.

ABSTRACT: Phosphatidylinositol 3-kinase ? (PI3K?) is a promising target for anticancer drug design. Oncogenic mutation H1047R in the catalytic domain is observed in many tumors and may enhance PI3K? kinase activity by affecting loop confirmations as well as membrane binding. We applied docking methods to 33 PI3K inhibitors against the wild type (wt) PI3K?, the H1047R mutant of PI3K? and the ? isoform of PI3K (PI3K?). We also investigated the effect of protein flexibility on ligand binding by docking the same set of ligands to conformations of the wt and mutant PI3K? generated by molecular dynamics simulations. Our data suggests that conformational differences in Gln859, Ser854, Tyr836, and Ser774 between the PI3K? wt and H1047R mutant may be used to design ligands that are active against both the wt and H1047R mutant isoforms. Gln859, Ser854 and Ser774 may play critical roles in ligand binding to the ? isoform H1047R mutant while formation of H-bonds with Ser806 of PI3K? may enhance ?-isoform-specific inhibition. In addition to H-bond interactions, structural and size differences in the activation and hydrophobic domains of PI3K?, PI3K?, and the PI3K? H1047R mutant could be exploited to direct the design of isoform- and/or mutant-specific PI3K inhibitors. Our data provide a reasonable explanation for the activity and selectivity of small molecular PI3K inhibitors and are in good agreement with available experimental and computational data.

SUBMITTER: Sabbah DA 

PROVIDER: S-EPMC4480772 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature