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

ACS Pharmacology & Translational Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Emerging evidence has demonstrated that cannabinoid receptor 2 (CB2) is involved in a number of diseases, such as neurodegenerative disorders and various types cancer, making it an attractive pharmacological target. Classically, protein active site or orthosteric binding site, where the endogenous ligand binds to, used target for design most small-molecule drugs. This can present challenges when comes to phylogenetically related proteins have similar sites, receptors. An alternative approach sites are unique these receptors yet still impact function, known allosteric sites. Using inactive-state human crystal structure (PDB ID:5ZTY), we identified putative CB2 using computational approaches. In vitro signaling assays modulators agonists been verify silico results. identification opens promising avenues development selective specific ligands therapeutic purposes.

Language: Английский

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Advances in cannabinoid receptors pharmacology: from receptor structural insights to ligand discovery

Acta Pharmacologica Sinica, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

Language: Английский

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Biased agonism of G protein-coupled receptors as a novel strategy for osteoarthritis therapy

Bone Research, Journal Year: 2025, Volume and Issue: 13(1)

Published: May 12, 2025

Abstract Osteoarthritis (OA) is a prevalent degenerative joint disorder marked by chronic pain, inflammation, and cartilage loss, with current treatments limited to symptom relief. G protein-coupled receptors (GPCRs) play pivotal role in OA progression regulating chondrocyte survival, matrix homeostasis. However, their multifaceted signaling, via proteins or β-arrestins, poses challenges for precise therapeutic targeting. Biased agonism, where ligands selectively activate specific GPCR pathways, emerges as promising approach optimize efficacy reduce side effects. This review examines biased signaling OA-associated GPCRs, including cannabinoid (CB 1 , CB 2 ), chemokine (CCR2, CXCR4), protease-activated (PAR-2), adenosine (A R, A 2A 2B 3 R), melanocortin (MC MC bradykinin (B prostaglandin E (EP-2, EP-4), calcium-sensing (CaSR). We analyze clinical trials explore natural products from Traditional Chinese Medicine potential agonists. These compounds, diverse structures bioactivities, offer novel avenues. By harnessing this underscores the developing targeted, safer therapies that address its complex pathology, bridging molecular insights translation.

Language: Английский

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GPCR-Mediated Natural Products and Compounds: Potential Therapeutic Targets for the Treatment of Neurological Diseases

Pharmacological Research, Journal Year: 2024, Volume and Issue: 208, P. 107395 - 107395

Published: Sept. 4, 2024

Language: Английский

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Differential Behavior of Conformational Dynamics in Active and Inactive States of Cannabinoid Receptor 1

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: 128(35), P. 8437 - 8447

Published: Aug. 22, 2024

Cannabinoid receptor 1 (CB1) is a G protein-coupled that regulates critical physiological processes including pain, appetite, and cognition. Understanding the conformational dynamics of CB1 associated with transitions between inactive active signaling states imperative for developing targeted modulators. Using microsecond-level all-atom molecular simulations, we identified marked differences in ensembles

Language: Английский

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Could positive allosteric modulators of the cannabinoid CB1 receptor be efficacious and safe for the treatment of chronic pain?

Current Opinion in Pharmacology, Journal Year: 2024, Volume and Issue: 79, P. 102495 - 102495

Published: Oct. 23, 2024

Language: Английский

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