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An Unusual Intramolecular Halogen Bond Guides Conformational Selection

2018; Wiley; Volume: 57; Issue: 31 Linguagem: Inglês

10.1002/anie.201804917

1521-3773

Roberta Tesch, Christian F. W. Becker, Matthias Müller, Michael E. Beck, Lena Quambusch, Matthäus Getlik, Jonas Lategahn, Niklas Uhlenbrock, Fanny N. Costa, Marcelo D. Polêto, Pedro de Sena Murteira Pinheiro, Daniel A. Rodrigues, Carlos Maurício R. Sant’Anna, Fábio Furlan Ferreira, Hugo Verli, Carlos Alberto Manssour Fraga, Daniel Rauh,

Organophosphorus compounds synthesis

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 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.