The structural determinants of the bitopic binding mode of a negative allosteric modulator of the dopamine D 2 receptor.

Autor: Draper-Joyce CJ; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 399 Royal Parade, Parkville, VIC 3052, Australia., Michino M; Computational Chemistry and Molecular Biophysics Unit, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, United States., Verma RK; Computational Chemistry and Molecular Biophysics Unit, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, United States., Klein Herenbrink C; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 399 Royal Parade, Parkville, VIC 3052, Australia., Shonberg J; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 399 Royal Parade, Parkville, VIC 3052, Australia., Kopinathan A; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 399 Royal Parade, Parkville, VIC 3052, Australia., Scammells PJ; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 399 Royal Parade, Parkville, VIC 3052, Australia., Capuano B; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 399 Royal Parade, Parkville, VIC 3052, Australia., Thal DM; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 399 Royal Parade, Parkville, VIC 3052, Australia., Javitch JA; Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute, New York, NY 10032, United States; Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute, New York, NY 10032, United States; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, United States., Christopoulos A; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 399 Royal Parade, Parkville, VIC 3052, Australia., Shi L; Computational Chemistry and Molecular Biophysics Unit, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, United States. Electronic address: lei.shi2@nih.gov., Lane JR; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 399 Royal Parade, Parkville, VIC 3052, Australia. Electronic address: rob.lane@monash.edu.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2018 Feb; Vol. 148, pp. 315-328. Date of Electronic Publication: 2018 Jan 09.
DOI: 10.1016/j.bcp.2018.01.002
Abstrakt: SB269652 is a negative allosteric modulator of the dopamine D 2 receptor (D 2 R) yet possesses structural similarity to ligands with a competitive mode of interaction. In this study, we aimed to understand the ligand-receptor interactions that confer its allosteric action. We combined site-directed mutagenesis with molecular dynamics simulations using both SB269652 and derivatives from our previous structure activity studies. We identify residues within the conserved orthosteric binding site (OBS) and a secondary binding pocket (SBP) that determine affinity and cooperativity. Our results indicate that interaction with the SBP is a requirement for allosteric pharmacology, but that both competitive and allosteric derivatives of SB269652 can display sensitivity to the mutation of a glutamate residue (E95 2.65 ) within the SBP. Our findings provide the molecular basis for the differences in affinity between SB269652 derivatives, and reveal how changes to interactions made by the primary pharmacophore of SB269652 in the orthosteric pocket can confer changes in the interactions made by the secondary pharmacophore in the SBP. Our insights provide a structure-activity framework towards rational optimization of bitopic ligands for D 2 R with tailored competitive versus allosteric properties.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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