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An Unusual Intramolecular Halogen Bond Guides Conformational Selection.
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.
Afiliación
  • Tesch R; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, 44227, Dortmund, Germany.
  • Becker C; Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho, 373, CEP, 21941-902, Rio de Janeiro, Brazil.
  • Müller MP; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, 44227, Dortmund, Germany.
  • Beck ME; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, 44227, Dortmund, Germany.
  • Quambusch L; Bayer AG, division Crop Science, Alfred-Nobel-Strasse 50, 40789, Monheim am Rhein, Germany.
  • Getlik M; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, 44227, Dortmund, Germany.
  • Lategahn J; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, 44227, Dortmund, Germany.
  • Uhlenbrock N; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, 44227, Dortmund, Germany.
  • Costa FN; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, 44227, Dortmund, Germany.
  • Polêto MD; Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, São Paulo, Brazil.
  • Pinheiro PSM; Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, 9500, Porto Alegre, Brazil.
  • Rodrigues DA; Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho, 373, CEP, 21941-902, Rio de Janeiro, Brazil.
  • Sant'Anna CMR; Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho, 373, CEP, 21941-902, Rio de Janeiro, Brazil.
  • Ferreira FF; Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho, 373, CEP, 21941-902, Rio de Janeiro, Brazil.
  • Verli H; Departamento de Química, Instituto de Ciências Exatas Universidade Federal Rural do Rio de Janeiro, Seropédica, Brazil.
  • Fraga CAM; Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, São Paulo, Brazil.
  • Rauh D; Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, 9500, Porto Alegre, Brazil.
Angew Chem Int Ed Engl ; 57(31): 9970-9975, 2018 07 26.
Article en En | MEDLINE | ID: mdl-29873877
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-3ß. The structure shows an unusual U-shaped conformation of PIK-75 within the active site of GSK-3ß 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Angew Chem Int Ed Engl Año: 2018 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Angew Chem Int Ed Engl Año: 2018 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Alemania