Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT1A Receptor |
| |
| Authors: | Dr Shuguang Yuan Dr Qian Peng Prof Krzysztof Palczewski Prof Horst Vogel Prof Slawomir Filipek |
| |
| Affiliation: | 1. Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland;2. Department of Chemistry, University of Oxford, UK;3. Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, USA;4. Laboratory of Biomodeling, Faculty of Chemistry & Biological and Chemical Research Centre, University of Warsaw, Warsaw, Poland |
| |
| Abstract: | G‐protein‐coupled receptors (GPCRs) are involved in a wide range of physiological processes, and they have attracted considerable attention as important targets for developing new medicines. A central and largely unresolved question in drug discovery, which is especially relevant to GPCRs, concerns ligand selectivity: Why do certain molecules act as activators (agonists) whereas others, with nearly identical structures, act as blockers (antagonists) of GPCRs? To address this question, we employed all‐atom, long‐timescale molecular dynamics simulations to investigate how two diastereomers (epimers) of dihydrofuroaporphine bind to the serotonin 5‐HT1A receptor and exert opposite effects. By using molecular interaction fingerprints, we discovered that the agonist could mobilize nearby amino acid residues to act as molecular switches for the formation of a continuous water channel. In contrast, the antagonist epimer remained firmly stabilized in the binding pocket. |
| |
| Keywords: | GPCRs molecular dynamics simulations proteins stereoselectivity water channels |
|
|
