title: Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D3Receptor.
abstract: Both dopamine D3receptor (D3R) partial agonists and antagonists have been implicated as potential medications for substance use disorders. In contrast to antagonists, partial agonists may cause fewer side effects since they maintain some dopaminergic tone and may be less disruptive to normal neuronal functions. Here, we report three sets of 4-phenylpiperazine stereoisomers that differ considerably in efficacy: the (R)-enantiomers are antagonists/weak partial agonists, whereas the (S)-enantiomers are much more efficacious. To investigate the structural basis of partial agonism, we performed comparative microsecond-scale molecular dynamics simulations starting from the inactive state of D3R in complex with these enantiomers. Analysis of the simulation results reveals common structural rearrangements near the ligand binding site induced by the bound (S)-enantiomers, but not by the (R)-enantiomers, that are features of partially activated receptor conformations. These receptor models bound with partial agonists may be useful for structure-based design of compounds with tailored efficacy profiles.
authors.affiliation: Computational Chemistry and Molecular Biophysics Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Mayako
authors.initials: M
authors.lastname: Michino
authors.affiliation: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.|Department of Basic Pharmaceutical Sciences, Fred Wilson School of Pharmacy, High Point University , One University Parkway, High Point, North Carolina 27268, United States.
authors.forename: Comfort A
authors.initials: CA
authors.lastname: Boateng
authors.affiliation: 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 10032, United States.
authors.forename: Prashant
authors.initials: P
authors.lastname: Donthamsetti
authors.affiliation: Computational Chemistry and Molecular Biophysics Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yano
authors.affiliation: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Oluyomi M
authors.initials: OM
authors.lastname: Bakare
authors.affiliation: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bonifazi
authors.affiliation: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Ellenberger
authors.affiliation: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.|Department of Chemistry and Biochemistry, and Department of Biomedical and Translational Sciences, College of Science and Mathematics, Rowan University , 201 Mullica Hill Road, Glassboro, New Jersey 08028, United States.
authors.forename: Thomas M
authors.identifier: 0000-0003-1845-9373
authors.initials: TM
authors.lastname: Keck
authors.affiliation: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Vivek
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Computational Chemistry and Molecular Biophysics Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Clare
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Computational Chemistry and Molecular Biophysics Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Ravi
authors.initials: R
authors.lastname: Verma
authors.affiliation: Naval Research Laboratory , Code 6930, 4555 Overlook Avenue, Washington, DC 20375, United States.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Deschamps
authors.affiliation: 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 10032, United States.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Javitch
authors.affiliation: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Amy Hauck
authors.identifier: 0000-0001-9065-4072
authors.initials: AH
authors.lastname: Newman
authors.affiliation: Computational Chemistry and Molecular Biophysics Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Lei
authors.identifier: 0000-0002-4137-096X
authors.initials: L
authors.lastname: Shi
mesh_terms: D001665:Binding Sites; D054333:Drug Partial Agonism; D057809:HEK293 Cells; D006801:Humans; D056004:Molecular Dynamics Simulation; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D010879:Piperazines; D050637:Receptors, Dopamine D3