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PLoS Comput Biol. 2018 Jan 16;14(1):e1005948. doi: 10.1371/journal.pcbi.1005948. eCollection 2018 Jan.

The E2.65A mutation disrupts dynamic binding poses of SB269652 at the dopamine D2 and D3 receptors.

Author information

1
Computational Chemistry and Molecular Biophysics Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, Baltimore, Maryland, United States.
2
Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States.
3
Departments of Psychiatry and Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York, United States.
4
Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, United States.
5
Drug Discovery Biology, Department of Pharmacology and Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), Parkville, Victoria, Australia.

Abstract

The dopamine D2 and D3 receptors (D2R and D3R) are important targets for antipsychotics and for the treatment of drug abuse. SB269652, a bitopic ligand that simultaneously binds both the orthosteric binding site (OBS) and a secondary binding pocket (SBP) in both D2R and D3R, was found to be a negative allosteric modulator. Previous studies identified Glu2.65 in the SBP to be a key determinant of both the affinity of SB269652 and the magnitude of its cooperativity with orthosteric ligands, as the E2.65A mutation decreased both of these parameters. However, the proposed hydrogen bond (H-bond) between Glu2.65 and the indole moiety of SB269652 is not a strong interaction, and a structure activity relationship study of SB269652 indicates that this H-bond may not be the only element that determines its allosteric properties. To understand the structural basis of the observed phenotype of E2.65A, we carried out molecular dynamics simulations with a cumulative length of ~77 μs of D2R and D3R wild-type and their E2.65A mutants bound to SB269652. In combination with Markov state model analysis and by characterizing the equilibria of ligand binding modes in different conditions, we found that in both D2R and D3R, whereas the tetrahydroisoquinoline moiety of SB269652 is stably bound in the OBS, the indole-2-carboxamide moiety is dynamic and only intermittently forms H-bonds with Glu2.65. Our results also indicate that the E2.65A mutation significantly affects the overall shape and size of the SBP, as well as the conformation of the N terminus. Thus, our findings suggest that the key role of Glu2.65 in mediating the allosteric properties of SB269652 extends beyond a direct interaction with SB269652, and provide structural insights for rational design of SB269652 derivatives that may retain its allosteric properties.

PMID:
29337986
PMCID:
PMC5786319
DOI:
10.1371/journal.pcbi.1005948
[Indexed for MEDLINE]
Free PMC Article

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