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
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.