title: Modeling of kappa-opioid receptor/agonists interactions using pharmacophore-based and docking simulations.
abstract: The interaction of the kappa-opioid receptor with arylacetamide and benzomorphan derivatives acting as agonists was modeled through pharmacophore-based and docking calculations. Potentially bioactive conformations of representative ligands (U-50,488 and its benzo-fused analogues 4 and 6 for arylacetamides and MPCB for benzomorphans) were identified by systematic conformational analysis and docked into a 3D model of the kappa-receptor. The obtained complexes, refined by energy-minimization and molecular dynamics, were evaluated for their consistency with structure-activity relationships and site-directed mutagenesis data. The following interactions are hypothesized to govern the ligand-receptor recognition process: (i) a salt bridge between the Asp138 carboxylate and the protonated nitrogen of the bound agonist; (ii) a hydrogen bond donated by the Tyr312 hydroxyl to the carbonyl oxygen of arylacetamides and MPCB; (iii) hydrophobic interactions established by the dichlorophenyl moiety of arylacetamides and the pendant phenyl ring of MPCB with the surrounding side chains of Tyr312, Leu224, Leu295, and Ala298; (iv) a pi-stacking contact between the Tyr312 side chain and the phenyl ring of arylacetamides; (v) a hydrogen bond linking the His291 imidazole ring to the phenolic hydroxy group featured by typical benzomorphans and the arylacetamides 4 and 6.
authors.affiliation: Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli "Federico II", Via D. Montesano 49, I-80131 Napoli, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Lavecchia
authors.forename: G
authors.initials: G
authors.lastname: Greco
authors.forename: E
authors.initials: E
authors.lastname: Novellino
authors.forename: F
authors.initials: F
authors.lastname: Vittorio
authors.forename: G
authors.initials: G
authors.lastname: Ronsisvalle
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000737:chemistry / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000737:chemistry / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D003496:Cyclazocine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D008968:Molecular Conformation; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: C110285:6,11-dimethyl-1,2,3,4,5,6-hexahydro-3-((2'-(methoxycarbonyl)-2'-phenylcyclopropyl)methyl)-2,6-methano-3-benzazocin-8-ol; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D003496:Cyclazocine