An Unusual Intramolecular Halogen Bond Guides Conformational Selection

Author(s):Show less -

Tesch, Roberta ^{[1, 2]} ; Becker, Christian ^[1] ; Mueller, Matthias Philipp ^[1] ; Beck, Michael Edmund ^[3] ; Quambusch, Lena ^[1] ; Getlik, Matthaus ^[1] ; Lategahn, Jonas ^[1] ; Uhlenbrock, Niklas ^[1] ; Costa, Fanny Nascimento ^[4] ; Poleto, Marcelo D. ^[5] ; Murteira Pinheiro, Pedro de Sena ^[2] ; Rodrigues, Daniel Alencar ^[2] ; Sant'Anna, Carlos Mauricio R. ^{[2, 6]} ; Ferreira, Fabio Furlan ^[4] ; Verli, Hugo ^[5] ; Manssour Fraga, Carlos Alberto ^[2] ; Rauh, Daniel ^[1]

Affiliation

^[1] TU Dortmund Univ, Fac Chem & Chem Biol, Otto Hahn Str 4a, D-44227 Dortmund - Germany

^[2] Univ Fed Rio de Janeiro, LASSBio, Inst Ciencias Biomed, Ave Carlos Chagas Filho, 373, BR-21941902 Rio De Janeiro - Brazil

^[3] Bayer AG, Div Crop Sci, Alfred Nobel Str 50, D-40789 Monheim - Germany

^[4] Univ Fed ABC, Ctr Ciencias Nat & Humanas, Sao Paulo - Brazil

^[5] Univ Fed Rio Grande do Sul, Ctr Biotecnol, Ave Bento Goncalves, BR-9500 Porto Alegre, RS - Brazil

^[6] Univ Fed Rural Rio de Janeiro, Dept Quim, Inst Ciencias Exatas, Seropedica - Brazil

• Document type: Journal article
• Source: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION; v. 57, n. 31, p. 9970-9975, JUL 26 2018.
• Web of Science Citations: 5

Abstract

PIK-75 is a phosphoinositide-3-kinase (PI3K) alpha-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-3 beta. The structure shows an unusual U-shaped conformation of PIK-75 within the active site of GSK-3 beta that is likely stabilized by an atypical intramolecular BrNO2 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. (AU)

• FAPESP's process: 15/26233-7 - Synthesis and structural characterization of cocrystals for application as sunscreen and antioxidants of topical use
• Grantee: Fabio Furlan Ferreira
• Support Opportunities: Regular Research Grants