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

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

SUBMITTER: Hurst DP 

PROVIDER: S-EPMC6691559 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature