Identification of CB1 Receptor Allosteric Sites Using Force-Biased MMC Simulated Annealing and Validation by Structure–Activity Relationship Studies

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Dow P. Hurst, Research Scientist (Creator)
Patricia H. Reggio, Professor and Department Head (Creator)
The University of North Carolina at Greensboro (UNCG )
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Abstract: Positive allosteric modulation of the cannabinoid 1 receptor (CB1R) has demonstrated distinct therapeutic advantages that address several limitations associated with orthosteric agonism and has opened a promising therapeutic avenue for further drug development. To advance the development of CB1R positive allosteric modulators, it is important to understand the molecular architecture of CB1R allosteric site(s). The goal of this work was to use Force-Biased MMC Simulated Annealing to identify binding sites for GAT228 (R), a partial allosteric agonist, and GAT229 (S), a positive allosteric modulator (PAM) at the CB1R. Our studies suggest that GAT228 binds in an intracellular (IC) TMH1–2–4 exosite that would allow this compound to act as a CB1 allosteric agonist as well as a CB1 PAM. In contrast, GAT229 binds at the extracellular (EC) ends of TMH2/3, just beneath the EC1 loop. At this site, this compound can act as CB1 PAM only. Finally, these results were successfully validated through the synthesis and biochemical evaluation of a focused library of compounds.

Additional Information

ACS Medicinal Chemistry Letters, 10(8), 1216-1221
Language: English
Date: 2019
CB1 cannabinoid receptor, PAM binding site, MMC simulated annealing, structure-activity relationship

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