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Cannabinoid receptor type 1 (CB1R) is a G protein-coupled receptor abundantly expressed in the central nervous system, where it regulates a wide range of physiological processes. However, targeting CB1R with orthosteric ligands has been associated with psychiatric side effects. Allosteric modulation offers an alternative approach, allowing selective receptor regulation with improved safety profiles. In this study, we designed a series of CB1R allosteric modulators based on the structure of the known CB1R allosteric ligand PSNCBAM-1. The binding affinity and interaction profiles of these compounds at the CB1R allosteric site were studied using both focused and blind molecular docking. Among the 16 designed derivatives, ligands 8 (–9.62 kcal/mol), 7 (–8.46 kcal/mol), and 4 (–8.04 kcal/mol) exhibited stronger binding affinities than PSNCBAM-1 (–7.17 kcal/mol). These findings highlight key structural features that govern CB1R allosteric modulation and pave the way for future structure–activity relationship and lead optimisation studies.

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In-Silico Identification of Novel Allosteric Modulators for Cannabinoid Receptor 1 (CB1R): Structural Optimisation of PSNCBAM-1

  • 会议论文

  • 发表日期：

    2026年

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  • Chek Kouk Kong,
  • Ghazi Al Jabal,
  • Mohamad Dayoob

摘要

Cannabinoid receptor type 1 (CB1R) is a G protein-coupled receptor abundantly expressed in the central nervous system, where it regulates a wide range of physiological processes. However, targeting CB1R with orthosteric ligands has been associated with psychiatric side effects. Allosteric modulation offers an alternative approach, allowing selective receptor regulation with improved safety profiles. In this study, we designed a series of CB1R allosteric modulators based on the structure of the known CB1R allosteric ligand PSNCBAM-1. The binding affinity and interaction profiles of these compounds at the CB1R allosteric site were studied using both focused and blind molecular docking. Among the 16 designed derivatives, ligands 8 (–9.62 kcal/mol), 7 (–8.46 kcal/mol), and 4 (–8.04 kcal/mol) exhibited stronger binding affinities than PSNCBAM-1 (–7.17 kcal/mol). These findings highlight key structural features that govern CB1R allosteric modulation and pave the way for future structure–activity relationship and lead optimisation studies.