ArticleProceedings of the National Academy of Sciences of the United States of America2024
Entropy drives the ligand recognition in G-protein-coupled receptor subtypes.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Dimethylindanoylindole Isomers Revealed Different Pharmacological Profiles at CB1 and CB2 Cannabinoid Receptors.ACS bio & med chem Au · 2026Article
- NAPE-PLD: the healthy intersection of N-acylethanolamines and bile acids in physiology and diseases.Pflugers Archiv : European journal of physiology · 2026Review
- Library Docking for Cannabinoid-2 Receptor Ligands.Journal of medicinal chemistry · 2026Article
- Dynamic mechanism for subtype selectivity of endocannabinoids.The Journal of biological chemistry · 2026Article
- From possibility to precision in macromolecular ensemble prediction.Nature methods · 2026Review
- Leveraging machine learning for selective cannabinoid ligand discovery: methods, challenges, and opportunities.Expert opinion on drug discovery · 2026Review
- A Reinforcement Learning-Guided Genetic Algorithm Integrating Medicinal Chemistry-Inspired Molecular Transformations.Journal of chemical information and modeling · 2026Article
- Library docking for Cannabinoid-2 Receptor ligands.bioRxiv : the preprint server for biology · 2026Article
- Article
- Crystallographic Ensembles Reveal the Structural Basis of Binding Entropy in SARS-CoV2 Macrodomain.bioRxiv : the preprint server for biology · 2025Article
- Nanoengineered Calcium Receptors Coupled with Microscale Thermophoresis Enable Sensitive, Low-Volume Quantification of Calcium Ions in Complex Biological Fluids.ACS sensors · 2025Article
- Advances in cannabinoid receptors pharmacology: from receptor structural insights to ligand discovery.Acta pharmacologica Sinica · 2025Review
- Temporal complexity of LVV-hemorphin-7 allosterism at the angiotensin II type 1 receptor assessed using entropy-based approaches.Computational and structural biotechnology journal · 2025Article
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21 authors.
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Abstract
Achieving ligand subtype selectivity within highly homologous subtypes of G-protein-coupled receptor (GPCR) is critical yet challenging for GPCR drug discovery, primarily due to the unclear mechanism underlying ligand subtype selectivity, which hampers the rational design of subtype-selective ligands. Herein, we disclose an unusual molecular mechanism of entropy-driven ligand recognition in cannabinoid (CB) receptor subtypes, revealed through atomic-level molecular dynamics simulations, cryoelectron microscopy structure, and mutagenesis experiments. This mechanism is attributed to the distinct conformational dynamics of the receptor's orthosteric pocket, leading to variations in ligand binding entropy and consequently, differential binding affinities, which culminate in specific ligand recognition. We experimentally validated this mechanism and leveraged it to design ligands with enhanced or ablated subtype selectivity. One such ligand demonstrated favorable pharmacokinetic properties and significant efficacy in rodent inflammatory analgesic models. More importantly, it is precisely due to the high subtype selectivity obtained based on this mechanism that this ligand does not show addictive properties in animal models. Our findings elucidate the unconventional role of entropy in CB receptor subtype selectivity and suggest a strategy for rational design of ligands to achieve entropy-driven subtype selectivity for many pharmaceutically important GPCRs.
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