How THC works: Explaining ligand affinity for, and partial agonism of, cannabinoid receptor 1
Summary: Interaction with cannabinoid receptor 1 (CB1) partially determines the bioactivity of the phytocannabinoids. Consequently, there has also been significant effort directed toward preparing synthetic cannabinoids with either enhanced agonistic or antagonistic activity against this receptor. T...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-07-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225009678 |
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| author | Farsheed Shahbazi-Raz Daniel Meister Azam Mohammadzadeh John Frederick Trant |
| author_facet | Farsheed Shahbazi-Raz Daniel Meister Azam Mohammadzadeh John Frederick Trant |
| author_sort | Farsheed Shahbazi-Raz |
| collection | DOAJ |
| description | Summary: Interaction with cannabinoid receptor 1 (CB1) partially determines the bioactivity of the phytocannabinoids. Consequently, there has also been significant effort directed toward preparing synthetic cannabinoids with either enhanced agonistic or antagonistic activity against this receptor. The design process of these molecules, and the identification of off-target effects at this receptor for molecules designed to target other proteins, would be aided by a reliable computational tool that can accurately predict binding. Furthermore, although the mechanism of CB1 agonism is understood, the conformational behavior that underlies the molecular mechanism of partial agonism is unclear. In this report, we provide a correction for calculating a ligand’s affinity to the orthosteric site of CB1 to account for their partition into membranes, use this to register the predicted affinity (high and low) of cannabinoids, and discuss how a mechanism for THC partial agonism arises natively from the model consistent with experimental data. |
| format | Article |
| id | doaj-art-1e8edfdebc3747cf91504cedaf9c51ec |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-1e8edfdebc3747cf91504cedaf9c51ec2025-08-20T03:50:05ZengElsevieriScience2589-00422025-07-0128711270610.1016/j.isci.2025.112706How THC works: Explaining ligand affinity for, and partial agonism of, cannabinoid receptor 1Farsheed Shahbazi-Raz0Daniel Meister1Azam Mohammadzadeh2John Frederick Trant3Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor ON N9B 3P4, Canada; Binary Star Research Services, LaSalle, ON N9J 3X8, Canada; Corresponding authorDepartment of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor ON N9B 3P4, Canada; Binary Star Research Services, LaSalle, ON N9J 3X8, Canada; Corresponding authorDepartment of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor ON N9B 3P4, CanadaDepartment of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor ON N9B 3P4, Canada; Binary Star Research Services, LaSalle, ON N9J 3X8, Canada; We-Spark Health Institute, 401 Sunset Avenue, Windsor ON N9B 3P4, Canada; Department of Biomedical Sciences, University of Windsor, 401 Sunset Avenue, Windsor ON N9B 3P4, Canada; Corresponding authorSummary: Interaction with cannabinoid receptor 1 (CB1) partially determines the bioactivity of the phytocannabinoids. Consequently, there has also been significant effort directed toward preparing synthetic cannabinoids with either enhanced agonistic or antagonistic activity against this receptor. The design process of these molecules, and the identification of off-target effects at this receptor for molecules designed to target other proteins, would be aided by a reliable computational tool that can accurately predict binding. Furthermore, although the mechanism of CB1 agonism is understood, the conformational behavior that underlies the molecular mechanism of partial agonism is unclear. In this report, we provide a correction for calculating a ligand’s affinity to the orthosteric site of CB1 to account for their partition into membranes, use this to register the predicted affinity (high and low) of cannabinoids, and discuss how a mechanism for THC partial agonism arises natively from the model consistent with experimental data.http://www.sciencedirect.com/science/article/pii/S2589004225009678Biological sciencesBiophysicsNatural sciencesPharmacoinformatics |
| spellingShingle | Farsheed Shahbazi-Raz Daniel Meister Azam Mohammadzadeh John Frederick Trant How THC works: Explaining ligand affinity for, and partial agonism of, cannabinoid receptor 1 iScience Biological sciences Biophysics Natural sciences Pharmacoinformatics |
| title | How THC works: Explaining ligand affinity for, and partial agonism of, cannabinoid receptor 1 |
| title_full | How THC works: Explaining ligand affinity for, and partial agonism of, cannabinoid receptor 1 |
| title_fullStr | How THC works: Explaining ligand affinity for, and partial agonism of, cannabinoid receptor 1 |
| title_full_unstemmed | How THC works: Explaining ligand affinity for, and partial agonism of, cannabinoid receptor 1 |
| title_short | How THC works: Explaining ligand affinity for, and partial agonism of, cannabinoid receptor 1 |
| title_sort | how thc works explaining ligand affinity for and partial agonism of cannabinoid receptor 1 |
| topic | Biological sciences Biophysics Natural sciences Pharmacoinformatics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225009678 |
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