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The cannabinoid receptor type 1 (CB1R), a class A G protein coupled receptor, represents a validated therapeutic target for pain, obesity, and neuropsychiatric disorders. However, orthosteric ligands often produce undesirable central effects that limit clinical utility. This study employed an integrated computational approach to identify novel CB1R allosteric modulators with improved safety profiles. Ligand based virtual screening of the ZINC drug like database using SwissSimilarity, guided by PSNCBAM-1, yielded 400 candidates. Molecular docking against the CB1R allosteric site (PDB 6KQI) identified nine compounds with superior binding affinity, among which ZINC72271965 demonstrated the most stable and favourable interactions with key residues TRP241, CYS238, HIS154, and PHE237. Molecular dynamics simulations confirmed stable receptor engagement and reduced structural fluctuations. ADMET and ProTox analyses indicated desirable pharmacokinetics and low toxicity. These findings highlight ZINC72271965 as a promising lead for CB1R modulation and a potential scaffold for safer central nervous system therapeutics.

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Identification of Potential CB1R Allosteric Modulators via Ligand-Based Similarity Search, Molecular Docking, ADMET Profiling and Molecular Dynamics Simulations

  • 会议论文

  • 发表日期：

    2026年

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  • Phang Yi Ying,
  • Ghazi Al Jabal,
  • Mohamad Anuar Ahad,
  • Kesevan Rajah Kumaran,
  • Mohamad Dayoob

摘要

The cannabinoid receptor type 1 (CB1R), a class A G protein coupled receptor, represents a validated therapeutic target for pain, obesity, and neuropsychiatric disorders. However, orthosteric ligands often produce undesirable central effects that limit clinical utility. This study employed an integrated computational approach to identify novel CB1R allosteric modulators with improved safety profiles. Ligand based virtual screening of the ZINC drug like database using SwissSimilarity, guided by PSNCBAM-1, yielded 400 candidates. Molecular docking against the CB1R allosteric site (PDB 6KQI) identified nine compounds with superior binding affinity, among which ZINC72271965 demonstrated the most stable and favourable interactions with key residues TRP241, CYS238, HIS154, and PHE237. Molecular dynamics simulations confirmed stable receptor engagement and reduced structural fluctuations. ADMET and ProTox analyses indicated desirable pharmacokinetics and low toxicity. These findings highlight ZINC72271965 as a promising lead for CB1R modulation and a potential scaffold for safer central nervous system therapeutics.