An Unusual Intramolecular Halogen Bond Guides Conformational Selection

Abstract

PIK-75 is a phosphoinositide-3-kinase (PI3K) α-isoform-selective inhibitor with high potency. Although published structure-activity relationship data show the importance of the NO₂ and the Br substituents in PIK-75, none of the published studies could correctly determine the underlying reason for their importance. In this publication, we report the first X-ray crystal structure of PIK-75 in complex with the kinase GSK-3β. The structure shows an unusual U-shaped conformation of PIK-75 within the active site of GSK-3β that is likely stabilized by an atypical intramolecular Br⋅⋅⋅NO₂ halogen bond. NMR and MD simulations show that this conformation presumably also exists in solution and leads to a binding-competent preorganization of the PIK-75 molecule, thus explaining its high potency. We therefore suggest that the site-specific incorporation of halogen bonds could be generally used to design conformationally restricted bioactive substances with increased potencies.

Keywords: PIK-75; glycogen synthase kinase-3β; halogen bonds; molecular dynamics; structure elucidation.