Exploring
a Non-ATP Pocket for Potential Allosteric
Modulation of PI3Kα
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Abstract
Allosteric modulators offer a novel
approach for kinase inhibition
because they target less conserved binding sites compared to the active
site; thus, higher selectivity may be obtained. PIK-108, a known pan
phosphoinositide 3-kinase (PI3K) inhibitor, was recently detected
to occupy a non-ATP binding site in the PI3Kα C-lobe. This newly
identified pocket is located close to residue 1047, which is frequently
mutated in human cancers (H1047R). In order to assess the interactions,
stability, and any possible allosteric effects of this inhibitor on
PI3Kα, extensive molecular dynamics (MD) simulations in aqueous
solution were performed for the wild type (WT) human, WT murine, and
H1047R human mutant PI3Kα proteins with PIK-108 placed in both
catalytic and non-ATP sites. We verify the existence of the second
binding site in the vicinity of the hotspot H1047R PI3Kα mutation
through binding site identification and MD simulations. PIK-108 remains
stable in both sites in all three variants throughout the course of
the simulations. We demonstrate that the pose and interactions of
PIK-108 in the catalytic site are similar in the murine WT and human
mutant forms, while they are significantly different in the case of
human WT PI3Kα protein. PIK-108 binding in the non-ATP pocket
also differs significantly among the three variants. Finally, we examine
whether the non-ATP binding site is implicated in PI3Kα allostery
in terms of its communication with the active site using principal
component analysis and perform in vitro experiments to verify our
hypotheses