An Unusual Intramolecular Halogen Bond Guides Conformational Selection

• DOI: 10.1002/anie.201804917
• Publication Date: 2018-06-06T15:32:28Z
• Authors: Roberta Tesch; Christian Becker; Matthias Philipp ...; Michael Edmund Beck; Lena Quambusch; Matthäus Getlik; Jonas Lategahn; Niklas Uhlenbrock; Fanny Nascimento ...; Marcelo D. Polêto; Pedro de Sena Mur...; Daniel Alencar Ro...; Carlos Mauricio R...; Fabio Furlan Ferr...; Hugo Verli; Carlos Alberto Ma...; Daniel Rauh
• Keywords: 0303 health sciences; 03 medical and health sciences

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 NO 2 and Br substituents in PIK‐75, none studies could correctly determine underlying reason for their importance. In this publication, we report first X‐ray crystal structure complex kinase GSK‐3β. The shows an unusual U‐shaped conformation within active site GSK‐3β that likely stabilized by atypical intramolecular Br⋅⋅⋅NO halogen bond. NMR MD simulations presumably also exists solution leads to binding‐competent preorganization molecule, thus explaining its We therefore suggest site‐specific incorporation bonds be generally used design conformationally restricted bioactive substances increased potencies.