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An Unusual Intramolecular Halogen Bond Guides Conformational Selection
Author(s) -
Tesch Roberta,
Becker Christian,
Müller Matthias Philipp,
Beck Michael Edmund,
Quambusch Lena,
Getlik Matthäus,
Lategahn Jonas,
Uhlenbrock Niklas,
Costa Fanny Nascimento,
Polêto Marcelo D.,
Pinheiro Pedro de Sena Murteira,
Rodrigues Daniel Alencar,
Sant'Anna Carlos Mauricio R.,
Ferreira Fabio Furlan,
Verli Hugo,
Fraga Carlos Alberto Manssour,
Rauh Daniel
Publication year - 2018
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201804917
Subject(s) - intramolecular force , chemistry , stereochemistry , active site , halogen , potency , gene isoform , crystal structure , crystallography , enzyme , biochemistry , gene , in vitro , alkyl , organic chemistry
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 NO 2 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⋅⋅⋅NO 2 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.