Identification of Subtype-Selective Binding Sites in the Opioid Receptor Family
Severo Gomes, Antoniel Augusto (Universitat Autònoma de Barcelona. Institut de Neurociències)
Guillot, Benoît (Université de Lorraine)
Jelsch, Christian (Université de Lorraine)
Giraldo, Jesús (Universitat Autònoma de Barcelona. Institut de Neurociències)

Date:	2026
Abstract:	Selectivity is essential in drug discovery for finding or developing more effective opioid modulators. Structure-based approaches and binding kinetics effectively identify potential druggable regions and determine ligand candidates for improved therapies. In this study, we combined molecular dynamics simulations and funnel-metadynamics with charge density analyses to identify unique structural aspects of the main opioid receptors (ORs), including the mu (μOR), delta (δOR), and kappa (κOR). We found distinct conformational dynamics between the receptors, with the κOR extracellular vestibule tending to form a lid that covers its orthosteric site. Furthermore, we investigated how morphinan-scaffold ligands with distinct pharmacological effects bind to OR orthosteric sites and extracellular vestibules, identifying intermediate ligand states. The lowest-energy states of each complex reproduced the morphinan-like orientation revealed by experimental structures and experimental free energy of binding. Moreover, we determined the role of orthosteric subpockets and extracellular loops (ECLs) in stabilizing ligand-bound states, shedding light on ligand selectivity. Our results provide a detailed description, from an energetic perspective, of the conformational dynamics and structure-based selectivity determination within the OR family. These regions can be rationally targeted for designing and developing functionally selective opioid modulators with improved pharmacological effects in pain treatment or other OR-related diseases.
Grants:	Agencia Estatal de Investigación PID2020-119136RB-I00
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	American Chemical Society ; Binding-sites ; Conformational dynamics ; Drug discovery ; Extracellular ; Opioid receptors ; Opioids ; Pharmacological effects ; Selective binding ; Structure-based ; Binding Sites ; Humans ; Ligands ; Molecular Dynamics Simulation ; Morphinans ; Protein Binding ; Protein Conformation ; Receptors, Opioid ; Thermodynamics
Published in:	Journal of chemical information and modeling, Vol. 66, Num. 8 (27 2026) , p. 4717-4733, ISSN 1549-960X

DOI: 10.1021/acs.jcim.5c02403

17 p, 11.0 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Neurociències (INc)
Articles > Research articles
Articles > Published articles