Structural Determinants of Buprenorphine Partial Agonism at the µ-Opioid Receptor
The mu-opioid receptor (mu OR) is a class A G Protein-Coupled Receptor (GPCR) targeted by natural and synthetic ligands to provide analgesia to patients with pain of various etiologies. Available opioid medications present several unwanted side effects, stressing the need for safer pain therapies. D...
| Autores: | , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Institut d'Investigació i Innovació Parc Taulí (I3PT) |
| Repositorio: | r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí |
| OAI Identifier: | oai:i3pt.fundanetsuite.com:p6471 |
| Acceso en línea: | https://i3pt.portalinvestigacion.com/publicaciones/6471 https://www.scopus.com/inward/record.uri?eid=2-s2.0-105004389284&doi=10.1021%2Facs.jcim.5c00078&partnerID=40&md5=4c23967b575c4870ae01e71ab5e3d77d |
| Access Level: | acceso abierto |
| Palabra clave: | Drug interactions Pharmacokinetics Agonisms Buprenorphine Dynamics simulation Metadynamics Opioid drugs Opioid receptors Opioids Salt bridges Side effect Structural aspects Binding sites buprenorphine ligand morphine mu opiate receptor narcotic analgesic agent protein binding chemistry human metabolism molecular docking molecular dynamics partial agonism protein conformation Analgesics, Opioid Drug Partial Agonism Humans Ligands Molecular Docking Simulation Molecular Dynamics Simulation Morphine Protein Binding Protein Conformation Receptors, Opioid, mu |
| Sumario: | The mu-opioid receptor (mu OR) is a class A G Protein-Coupled Receptor (GPCR) targeted by natural and synthetic ligands to provide analgesia to patients with pain of various etiologies. Available opioid medications present several unwanted side effects, stressing the need for safer pain therapies. Despite the attractive proposal that biasing mu OR signaling toward G protein pathways would lead to fewer side effects, recent studies indicate that low-efficacy opioid drugs, such as buprenorphine, may represent a safer alternative. In the present work, we combine molecular docking, microsecond-time scale molecular dynamics (MD) simulations, and metadynamics to investigate the conformational dynamics of the mu OR bound to morphine or buprenorphine. Our objective was to determine structural aspects associated with the unique pharmacological effects caused by the latter, taking morphine as a reference. MD simulations identified a salt bridge with D1493.32 as crucial for stabilizing both ligands into the mu OR orthosteric site, with this interaction being weaker in buprenorphine. The morphinan-scaffold of both ligands shared contacts with transmembrane (TM) helix residues of the receptor, including TM3, TM5, TM6, and TM7. Conversely, while morphine showed stronger interactions with a few TM3 residues, additional chemical groups of buprenorphine showed stronger interactions with TM2, extracellular loop 2 (ECL2), and TM7 residues. We also observed distinct TM arrangements induced by these ligands, with buprenorphine causing an extracellular outward movement of TM7 and morphine provoking intracellular inward movements of TM5 and TM7 of the receptor. In addition, we found that buprenorphine tends to explore deeper regions in the mu OR orthosteric site, further supported by funnel-metadynamics, resulting in diverse side chain orientations of W2956.48. Metadynamics also unveiled distinct intermediate states for morphine and buprenorphine, with the latter accessing a secondary binding site associated with partial mu OR agonists. Our results indicate that the weakened salt bridge of buprenorphine with D1493.32, along with the strong TM7 interaction through its cyclopropyl group, may explain its low efficacy and consequent partial mu OR agonism. Furthermore, ECL2 interactions may contribute to explaining the biased agonism of buprenorphine, a common feature shared with other opioid modulators with similar functional effects. Our study sheds light on the complex pharmacology of buprenorphine, identifying structural aspects associated with its partial and biased mu OR agonism. These results can provide valuable information for the design of new effective and safer opioid drugs. |
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