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The cannabinoid receptor type 1 (CB1R) is a critical therapeutic target involved in pain regulation, metabolic control, and the treatment of neurodegenerative conditions. However, the neuropsychiatric complications of orthosteric ligands have constrained their clinical translation. Allosteric modulation offers a refined strategy to regulate receptor function while preserving endocannabinoid signalling. In this study, a pharmacophore-based virtual screening employing Org27569 as a reference was performed on more than seventeen million compounds from the ZINC15 and MolPort databases. Molecular docking against the CB1R allosteric site (PDB 6KQI) identified fifteen hits with higher affinity values ranging from −8.33 to −9.23 kcal/mol. Among these, ZINC13688610 exhibited optimal pocket complementarity, favourable ADMET features, and a non-toxic profile. Molecular dynamics simulations over 50 ns further confirmed stable engagement within the allosteric site. These findings identify ZINC13688610 as a promising candidate for selective CB1R allosteric modulation and warrant further biochemical and functional evaluation to validate its therapeutic potential.

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Pharmacophore Modelling, Virtual Screening, and Molecular Dynamics Simulation of Novel CB1R Allosteric Modulators

  • 会议论文

  • 发表日期：

    2026年

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  • Brenda Chia Ming Yee,
  • Ghazi Al Jabal,
  • Mohamad Dayoob

摘要

The cannabinoid receptor type 1 (CB1R) is a critical therapeutic target involved in pain regulation, metabolic control, and the treatment of neurodegenerative conditions. However, the neuropsychiatric complications of orthosteric ligands have constrained their clinical translation. Allosteric modulation offers a refined strategy to regulate receptor function while preserving endocannabinoid signalling. In this study, a pharmacophore-based virtual screening employing Org27569 as a reference was performed on more than seventeen million compounds from the ZINC15 and MolPort databases. Molecular docking against the CB1R allosteric site (PDB 6KQI) identified fifteen hits with higher affinity values ranging from −8.33 to −9.23 kcal/mol. Among these, ZINC13688610 exhibited optimal pocket complementarity, favourable ADMET features, and a non-toxic profile. Molecular dynamics simulations over 50 ns further confirmed stable engagement within the allosteric site. These findings identify ZINC13688610 as a promising candidate for selective CB1R allosteric modulation and warrant further biochemical and functional evaluation to validate its therapeutic potential.