title: Mechanistic Studies on the Stereoselectivity of the Serotonin 5-HT1A Receptor.
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.
authors.affiliation: Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. shuguang.yuan@gmail.com.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Department of Chemistry, University of Oxford, UK.
authors.forename: Qian
authors.initials: Q
authors.lastname: Peng
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
authors.affiliation: Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Horst
authors.initials: H
authors.lastname: Vogel
authors.affiliation: Laboratory of Biomodeling, Faculty of Chemistry & Biological and Chemical Research Centre, University of Warsaw, Warsaw, Poland. sfilipek@chem.uw.edu.pl.
authors.forename: Slawomir
authors.initials: S
authors.lastname: Filipek
mesh_terms: D001060:Aporphines / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000737:chemistry / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: D001060:Aporphines; D008024:Ligands; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D014867:Water; D044282:Receptor, Serotonin, 5-HT1A
keywords: GPCRs; molecular dynamics simulations; proteins; stereoselectivity; water channels