Identification of a Cannabinoid Receptor 2 Allosteric Site Using Computational Modeling and Pharmacological Analysis

Farooq, Zara, Delre, Pietro, Iliadis, Stylianos, Mangiatordi, Giuseppe Felice, Contino, Marialessandra, Howell, Lesley A and McCormick, Peter J ORCID: 0000-0002-2225-5181 (2025) Identification of a Cannabinoid Receptor 2 Allosteric Site Using Computational Modeling and Pharmacological Analysis ACS Pharmacology & Translational Science, 8 (2). pp. 423-434. ISSN 2575-9108, 2575-9108

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Abstract

Emerging evidence has demonstrated that cannabinoid receptor 2 (CB<inf>2</inf>) is involved in a number of diseases, such as neurodegenerative disorders and various types of cancer, making it an attractive pharmacological target. Classically, a protein active site or an orthosteric binding site, where the endogenous ligand binds to, is used as a target for the design of most small-molecule drugs. This can present challenges when it comes to phylogenetically related proteins that have similar orthosteric binding sites, such as the cannabinoid receptors. An alternative approach is to target sites that are unique to these receptors yet still impact receptor function, known as allosteric binding sites. Using an inactive-state human cannabinoid receptor 2 crystal structure (PDB ID:5ZTY), we identified a putative CB<inf>2</inf> allosteric site using computational approaches. In vitro signaling assays using known allosteric modulators and CB<inf>2</inf> agonists have been used to verify the in silico results. This identification opens promising avenues for the development of selective and specific CB<inf>2</inf> ligands for therapeutic purposes.

Item Type:	Article
Uncontrolled Keywords:	cannabinoid receptor 2 (CB2), G protein-coupledreceptor (GPCR), allosteric, computational, signaling
Divisions:	Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	07 Feb 2025 11:39
Last Modified:	28 Feb 2026 07:31
DOI:	10.1021/acsptsci.4c00547
Open Access URL:	https://doi.org/10.1021/acsptsci.4c00547
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3190187
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