Complementarity of ? opioid ligand pharmacophore and receptor models

Abstract

The elaboration of a pharmacophore model for the ␦ opioid receptor selective ligand OH) and the parallel, independent development of a structural model of the ␦ receptor are summarized. Although the backbone conformation of JOM-13's tripeptide cycle is well defined, considerable conformational lability is evident in the Tyr 1 residue and in the Phe 3 side chain, key pharmacophore elements of the ligand. Replacement of these flexible features of the ligand by more conformationally restricted analogues and subsequent correlation of receptor binding and conformational properties allowed the number of possible binding conformations of JOM-13 to be reduced to two. Of these, one was chosen as more likely, based on its better superposition with other conformationally constrained ␦ receptor ligands. Our model of the ␦ opioid receptor, constructed using a general approach that we have developed for all rhodopsin-like G protein-coupled receptors, contains a large cavity within the transmembrane domain that displays excellent complementarity in both shape and polarity to JOM-13 and other ␦ ligands. This binding pocket, however, cannot accommodate the conformer of JOM-13 preferred from analysis of ligands, alone. Rather, only the "alternate" allowed conformer, identified from analysis of the ligands but "disfavored" because it does not permit simultaneous superposition of all pharmacophore elements of JOM-13 with other ␦ ligands, fits the binding site. These results argue against a simple view of a single, common fit to a receptor binding site and suggest, instead, that at least some binding site interactions of different ligands may differ.

Conformationally constrained opioid ligands: The Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold

“…3A) and of the known μ-agonist JOM6 (Tyr 1 -c(S-Et-S)[D-Cys 2 -Phe 3 -d-Pen4]NH 2 ) in MOR (Fig. 4A) which are in line with experimental studies 22, 23, 26–34. In both receptors, the protonated amine group of the ligand forms a complementary H-bond interaction network with D3.3228, 31 (Ballesteros-Weinstein numbering) and Y7.43,30, 31 while the Tyr 1 phenol ring binds in the hydrophobic pocket between Y3.3330, 33 and W6.4830 and forms an H-bond with H6.52 26.…”

“…3B) and 5 (in MOR, see Fig. 4B) involved in the same receptor-ligand interactions as JOM1323 (in DOR, Fig. 3A) and JOM622 (in MOR, Fig.…”

“…Three-dimensional structural models of the δ-opioid (DOR) and μ-opioid receptor (MOR) were constructed and refined according to a GPCR modeling procedure previously described,20 using the beta 2 adrenergic receptor crystal structure21 as a homology modeling template and using the experimental constraints defined by Mosberg et al22, 23 Surflex24 automated docking simulations25 yielded binding modes of the known δ-agonist JOM13 (Tyr 1 -c[D-Cys 2 -Phe 3 -D-Pen 4 ]OH) in DOR (Fig. 3A) and of the known μ-agonist JOM6 (Tyr 1 -c(S-Et-S)[D-Cys 2 -Phe 3 -d-Pen4]NH 2 ) in MOR (Fig.…”

“…In both receptors, the protonated amine group of the ligand forms a complementary H-bond interaction network with D3.3228, 31 (Ballesteros-Weinstein numbering) and Y7.43,30, 31 while the Tyr 1 phenol ring binds in the hydrophobic pocket between Y3.3330, 33 and W6.4830 and forms an H-bond with H6.52 26. The Phe3 group of JOM6 adopts a trans χ 1 orientation and forms aromatic interactions with W7.35 in MOR,22 while the Phe3 group of JOM13 adopts a gauche (+) orientation and binds in the hydrophobic pocket near H7.36 in DOR 23. The C-terminal carboxamide group of JOM6 is in close proximity of E5.35 in MOR,22 whereas the C-terminal carboxylate group of JOM13 forms a salt bridge with K5.39 in DOR 23.…”

“…The Phe3 group of JOM6 adopts a trans χ 1 orientation and forms aromatic interactions with W7.35 in MOR,22 while the Phe3 group of JOM13 adopts a gauche (+) orientation and binds in the hydrophobic pocket near H7.36 in DOR 23. The C-terminal carboxamide group of JOM6 is in close proximity of E5.35 in MOR,22 whereas the C-terminal carboxylate group of JOM13 forms a salt bridge with K5.39 in DOR 23. Docking poses25 of reference compounds 4 (in DOR, see Fig.…”