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Molecular determinants of recognition and activation at the μ‐opioid receptor by met‐enkephalin‐like peptides
Author(s) -
Perez Juan J.,
Villar Hugo O.,
Uyeno Ed,
Toll Lawrence,
Olsen Christopher,
Polgar Wilma,
Loew Gilda H.
Publication year - 1993
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.560480717
Subject(s) - pharmacophore , conformational isomerism , chemistry , molecular recognition , stereochemistry , moiety , molecular dynamics , molecular mechanics , peptide , receptor , opioid receptor , combinatorial chemistry , biochemistry , computational chemistry , molecule , agonist , organic chemistry
In this study, the techniques of computational chemistry were used to probe the origin of the differing pharmacological profiles found as a result of two simple modifications of the enkephalin analog Tyr–DAla–Gly–Phe–MetNH 2 : the presence or absence of N ‐methylation of Phe 4 and of the Met 5 residue. Although all four analogs have high μ‐receptor affinity, their analgesic activity varies by a factor of 3000. Thus, they should share common determinants of μ‐receptor recognition while differing in the ability to activate the receptor. To identify and characterize these determinants, a two‐step procedure was used. In the first step, the energy conformational profile of each peptide was obtained. The strategy used involved the iterative calculation of molecular dynamics trajectories at high and low temperatures, coupled to energy minimizations, allowing a through sampling of conformational space. In the second step, low‐energy conformers of the four peptides were examined for the extent to which they fulfilled the requirements for μ‐receptor recognition recently developed for nonpeptide analogs. In these studies, the amine nitrogen, a second proton‐accepting moiety, and an aromatic ring in a specific geometric arrangement were proposed as the minimum components of a μ‐pharmacophore for recognition. For all four analogs, a unique low‐energy conformer was found that contained these three recognition moieties in a geometric arrangement to interact with the same target binding site residues as in the nonpeptide analogs. These results are consistent with the finding of high affinity for all four peptides and provide common determinants of recognition of the μ‐receptor by peptides and nonpeptides. When the four peptides were overlapped so that they could each interact with these three common recognition sites, the Phe 4 aromatic side chain was found to be a possible modulator of activation. For the parent pentapeptide, Tyr–DAla–Gly–Phe–Met, with the lowest activity, there was poor overlap of the Phe 4 aromatic ring with the same ring in the other three analogs. These results implicate the Phe 4 ring in peptide activation of the μ‐receptor. © 1993 John Wiley & Sons, Inc.