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

ABSTRACT: Phosphatidylinositol 3-kinase α (PI3Kα) is a promising target for anticancer drug design. Oncogenic mutation H1047R in the catalytic domain is observed in many tumors and may enhance PI3Kα kinase activity by affecting loop confirmations as well as membrane binding. We applied docking methods to 33 PI3K inhibitors against the wild type (wt) PI3Kα, the H1047R mutant of PI3Kα and the γ isoform of PI3K (PI3Kγ). 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 PI3Kα generated by molecular dynamics simulations. Our data suggests that conformational differences in Gln859, Ser854, Tyr836, and Ser774 between the PI3Kα wt and H1047R mutant may be used to design ligands that are active against both the wt

SUBMITTER: Sabbah DA 

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

REPOSITORIES: biostudies-literature