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Review ArticleReview Article

What Can Crystal Structures of Aminergic Receptors Tell Us about Designing Subtype-Selective Ligands?

Mayako Michino, Thijs Beuming, Prashant Donthamsetti, Amy Hauck Newman, Jonathan A. Javitch and Lei Shi
David R. Sibley, ASSOCIATE EDITOR
Pharmacological Reviews January 2015, 67 (1) 198-213; DOI: https://doi.org/10.1124/pr.114.009944
Mayako Michino
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.)
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Thijs Beuming
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.)
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Prashant Donthamsetti
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.)
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Amy Hauck Newman
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.)
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Jonathan A. Javitch
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.)
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Lei Shi
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.)
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David R. Sibley
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.)
Roles: ASSOCIATE EDITOR
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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.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute on Drug Abuse [Grants K05-DA022413 (to J.A.J.) and R00-DA023694 (to L.S.)]; the National Institutes of Health National Institute of Mental Health [Grant R01-MH54137 (to J.A.J.)]; Lieber Center for Schizophrenia Research and Training; and the Intramural Research Program of the National Institutes of Health [National Institute on Drug Abuse] (to A.H.N.).

  • dx.doi.org/10.1124/pr.114.009944.

  • U.S. Government work not protected by U.S. copyright
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Pharmacological Reviews: 67 (1)
Pharmacological Reviews
Vol. 67, Issue 1
1 Jan 2015
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Review ArticleReview Article

Rational Design of Selective Ligands for Aminergic Receptors

Mayako Michino, Thijs Beuming, Prashant Donthamsetti, Amy Hauck Newman, Jonathan A. Javitch and Lei Shi
Pharmacological Reviews January 1, 2015, 67 (1) 198-213; DOI: https://doi.org/10.1124/pr.114.009944

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Review ArticleReview Article

Rational Design of Selective Ligands for Aminergic Receptors

Mayako Michino, Thijs Beuming, Prashant Donthamsetti, Amy Hauck Newman, Jonathan A. Javitch and Lei Shi
Pharmacological Reviews January 1, 2015, 67 (1) 198-213; DOI: https://doi.org/10.1124/pr.114.009944
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  • Article
    • Abstract
    • I. Introduction
    • II. Ligand Binding Pockets Revealed by Crystal Structures of Aminergic Receptors
    • III. Mechanisms for Achieving Subtype Selectivity
    • IV. Conclusions
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