Journal
BIOCHEMICAL PHARMACOLOGY
Volume 148, Issue -, Pages 315-328Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2018.01.002
Keywords
G protein-coupled receptor; Dopamine receptor; Allosteric modulation; Bitopic ligands; Molecular dynamics simulations; Mutagenesis
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Funding
- National Health and Medical Research Council (NHMRC) [1049564]
- NHMRC [1055134]
- Intramural Research Program of the National Institutes of Health, National Institute on Drug Abuse
- Australian Postgraduate Awards
- NATIONAL INSTITUTE ON DRUG ABUSE [ZIADA000606] Funding Source: NIH RePORTER
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SB269652 is a negative allosteric modulator of the dopamine D-2 receptor (D2R) 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 D2R with tailored competitive versus allosteric properties. (C) 2018 Elsevier Inc. All rights reserved.
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