Modeling of kappa-opioid receptor/agonists interactions using pharmacophore-based and docking simulations

Citation
A. Lavecchia et al., Modeling of kappa-opioid receptor/agonists interactions using pharmacophore-based and docking simulations, J MED CHEM, 43(11), 2000, pp. 2124-2134
Citations number
68
Categorie Soggetti
Chemistry & Analysis
Journal title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN journal
00222623 → ACNP
Volume
43
Issue
11
Year of publication
2000
Pages
2124 - 2134
Database
ISI
SICI code
0022-2623(20000601)43:11<2124:MOKRIU>2.0.ZU;2-5
Abstract
The interaction of the kappa-opioid receptor with arylacetamide and benzomo rphan derivatives acting as agonists was modeled through pharmacophore-base d and docking calculations. Potentially bioactive conformations of represen tative ligands (U-50,488 and its benzo-fused analogues 4 and 6 for arylacet amides and MPCB for benzomorphans) were identified by systematic conformati onal analysis and docked into a 3D model of the kappa-receptor. The obtaine d complexes, refined by energy-minimization and molecular dynamics, were ev aluated for their consistency with structure-activity relationships and sit e-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; (i i) 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 MPC B 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 t o the phenolic hydroxy group featured by typical benzomorphans and the aryl acetamides 4 and 6.