An Unusual Intramolecular Halogen Bond Guides Conformational Selection.
Roberta TeschChristian BeckerMatthias Philipp MüllerMichael Edmund BeckLena QuambuschMatthäus GetlikJonas LategahnNiklas UhlenbrockFanny Nascimento CostaMarcelo D PolêtoPedro de Sena Murteira PinheiroDaniel Alencar RodriguesCarlos Mauricio R Sant'AnnaFabio Furlan FerreiraHugo VerliCarlos Alberto Manssour FragaDaniel RauhPublished in: Angewandte Chemie (International ed. in English) (2018)
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-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⋅⋅⋅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.
Keyphrases
- molecular dynamics
- molecular dynamics simulations
- high resolution
- structure activity relationship
- signaling pathway
- magnetic resonance
- protein kinase
- tyrosine kinase
- randomized controlled trial
- energy transfer
- drinking water
- computed tomography
- single molecule
- crystal structure
- machine learning
- magnetic resonance imaging
- cell proliferation
- transition metal
- case control
- dual energy