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SPR-based fragment screening with neurotensin receptor 1 generates novel small molecule ligands.
Huber, Sylwia; Casagrande, Fabio; Hug, Melanie N; Wang, Lisha; Heine, Philipp; Kummer, Lutz; Plückthun, Andreas; Hennig, Michael.
  • Huber S; Roche Innovation Center Basel, Pharmaceutical Research and Early Development, Basel, Switzerland.
  • Casagrande F; Roche Innovation Center Basel, Pharmaceutical Research and Early Development, Basel, Switzerland.
  • Hug MN; Roche Innovation Center Basel, Pharmaceutical Research and Early Development, Basel, Switzerland.
  • Wang L; Roche Innovation Center Basel, Pharmaceutical Research and Early Development, Basel, Switzerland.
  • Heine P; Department of Biochemistry, University of Zurich, Zurich, Switzerland.
  • Kummer L; Department of Biochemistry, University of Zurich, Zurich, Switzerland.
  • Plückthun A; Department of Biochemistry, University of Zurich, Zurich, Switzerland.
  • Hennig M; Roche Innovation Center Basel, Pharmaceutical Research and Early Development, Basel, Switzerland.
PLoS One ; 12(5): e0175842, 2017.
Article en En | MEDLINE | ID: mdl-28510609
ABSTRACT
The neurotensin receptor 1 represents an important drug target involved in various diseases of the central nervous system. So far, the full exploitation of potential therapeutic activities has been compromised by the lack of compounds with favorable physicochemical and pharmacokinetic properties which efficiently penetrate the blood-brain barrier. Recent progress in the generation of stabilized variants of solubilized neurotensin receptor 1 and its subsequent purification and successful structure determination presents a solid starting point to apply the approach of fragment-based screening to extend the chemical space of known neurotensin receptor 1 ligands. In this report, surface plasmon resonance was used as primary method to screen 6369 compounds. Thereby 44 hits were identified and confirmed in competition as well as dose-response experiments. Furthermore, 4 out of 8 selected hits were validated using nuclear magnetic resonance spectroscopy as orthogonal biophysical method. Computational analysis of the compound structures, taking the known crystal structure of the endogenous peptide agonist into consideration, gave insight into the potential fragment-binding location and interactions and inspires chemistry efforts for further exploration of the fragments.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Receptores de Neurotensina / Bibliotecas de Moléculas Pequeñas / Descubrimiento de Drogas Tipo de estudio: Diagnostic_studies / Prognostic_studies / Screening_studies Límite: Humans Idioma: En Año: 2017 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Receptores de Neurotensina / Bibliotecas de Moléculas Pequeñas / Descubrimiento de Drogas Tipo de estudio: Diagnostic_studies / Prognostic_studies / Screening_studies Límite: Humans Idioma: En Año: 2017 Tipo del documento: Article