title: What can crystal structures of aminergic receptors tell us about designing subtype-selective ligands?
abstract: G protein-coupled receptors (GPCRs) are integral membrane proteins that represent an important class of drug targets. In particular, aminergic GPCRs interact with a significant portion of drugs currently on the market. However, most drugs that target these receptors are associated with undesirable side effects, which are due in part to promiscuous interactions with close homologs of the intended target receptors. Here, based on a systematic analysis of all 37 of the currently available high-resolution crystal structures of aminergic GPCRs, we review structural elements that contribute to and can be exploited for designing subtype-selective compounds. We describe the roles of secondary binding pockets (SBPs), as well as differences in ligand entry pathways to the orthosteric binding site, in determining selectivity. In addition, using the available crystal structures, we have identified conformational changes in the SBPs that are associated with receptor activation and explore the implications of these changes for the rational development of selective ligands with tailored efficacy.
authors.affiliation: Department of Physiology and Biophysics and Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, New York (M.M., L.S.); Schrödinger Inc., New York, New York (T.B.); Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons, and Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York (P.D., J.A.J.); and Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, Baltimore, Maryland (A.H.N.).
authors.forename: Mayako
authors.initials: M
authors.lastname: Michino
authors.affiliation: Department of Physiology and Biophysics and Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, New York (M.M., L.S.); Schrödinger Inc., New York, New York (T.B.); Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons, and Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York (P.D., J.A.J.); and Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, Baltimore, Maryland (A.H.N.).
authors.forename: Thijs
authors.initials: T
authors.lastname: Beuming
authors.affiliation: Department of Physiology and Biophysics and Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, New York (M.M., L.S.); Schrödinger Inc., New York, New York (T.B.); Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons, and Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York (P.D., J.A.J.); and Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, Baltimore, Maryland (A.H.N.).
authors.forename: Prashant
authors.initials: P
authors.lastname: Donthamsetti
authors.affiliation: Department of Physiology and Biophysics and Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, New York (M.M., L.S.); Schrödinger Inc., New York, New York (T.B.); Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons, and Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York (P.D., J.A.J.); and Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, Baltimore, Maryland (A.H.N.).
authors.forename: Amy Hauck
authors.initials: AH
authors.lastname: Newman
authors.affiliation: Department of Physiology and Biophysics and Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, New York (M.M., L.S.); Schrödinger Inc., New York, New York (T.B.); Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons, and Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York (P.D., J.A.J.); and Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, Baltimore, Maryland (A.H.N.).
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Javitch
authors.affiliation: Department of Physiology and Biophysics and Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, New York (M.M., L.S.); Schrödinger Inc., New York, New York (T.B.); Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons, and Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York (P.D., J.A.J.); and Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, Baltimore, Maryland (A.H.N.) les2007@med.cornell.edu.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
mesh_terms: D000588:Amines / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003461:Crystallography; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D008024:Ligands; D043562:Receptors, G-Protein-Coupled