title: Allosteric modulation model of the mu opioid receptor by herkinorin, a potent not alkaloidal agonist.
abstract: Modulation of opioid receptors is the primary choice for pain management and structural information studies have gained new horizons with the recently available X-ray crystal structures. Herkinorin is one of the most remarkable salvinorin A derivative with high affinity for the mu opioid receptor, moderate selectivity and lack of nitrogen atoms on its structure. Surprisingly, binding models for herkinorin are lacking. In this work, we explore binding models of herkinorin using automated docking, molecular dynamics simulations, free energy calculations and available experimental information. Our herkinorin D-ICM-1 binding model predicted a binding free energy of -11.52 ± 1.14 kcal mol-1by alchemical free energy estimations, which is close to the experimental values -10.91 ± 0.2 and -10.80 ± 0.05 kcal mol-1and is in agreement with experimental structural information. Specifically, D-ICM-1 molecular dynamics simulations showed a water-mediated interaction between D-ICM-1 and the amino acid H2976.52, this interaction coincides with the co-crystallized ligands. Another relevant interaction, with N1272.63, allowed to rationalize herkinorin's selectivity to mu over delta opioid receptors. Our suggested binding model for herkinorin is in agreement with this and additional experimental data. The most remarkable observation derived from our D-ICM-1 model is that herkinorin reaches an allosteric sodium ion binding site near N1503.35. Key interactions in that region appear relevant for the lack of β-arrestin recruitment by herkinorin. This interaction is key for downstream signaling pathways involved in the development of side effects, such as tolerance. Future SAR studies and medicinal chemistry efforts will benefit from the structural information presented in this work.
authors.affiliation: Instituto de Química, Universidad Nacional Autónoma de México, Av. Universidad 3000, 04510, Mexico City, Mexico.
authors.forename: A F
authors.initials: AF
authors.lastname: Marmolejo-Valencia
authors.affiliation: Instituto de Química, Universidad Nacional Autónoma de México, Av. Universidad 3000, 04510, Mexico City, Mexico. kmtzm@unam.mx.
authors.forename: K
authors.initials: K
authors.lastname: Martínez-Mayorga
mesh_terms: D000494:Allosteric Regulation; D000596:Amino Acids / Q000737:chemistry; D001665:Binding Sites; D005663:Furans / Q000737:chemistry*; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D011753:Pyrones / Q000737:chemistry*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: C502982:9-(benzoyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho(2,1-c)pyran-7-carboxylic acid methyl ester; D000596:Amino Acids; D005663:Furans; D008024:Ligands; D011753:Pyrones; D017450:Receptors, Opioid, mu
keywords: Allosteric binding; Biased agonist; Functional selectivity; Herkinorin; Mu opioid receptor