Homology modeling of opioid receptor-ligand complexes using experimental constraints

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Homology modeling of opioid receptor-ligand complexes using experimental constraints

Journal Title: The AAPS Journal - Year 2005, Vol 7, Issue 2

Abstract

Opioid receptors interact with a variety of ligands, including endogenous peptides, opiates, and thousands of synthetic compounds with different structural scaffolds. In the absence of experimental structures of opioid receptors, theoretical modeling remains an important tool for structurefunction analysis. The combination of experimental studies and modeling approaches allows development of realistic models of ligand-receptor complexes helpful for elucidation of the molecular determinants of ligand affinity and selectivity and for understanding mechanisms of functional agonism or antagonism. In this review we provide a brief critical assessment of the status of such theoretical modeling and describe some common problems and their possible solutions. Currently, there are no reliable theoretical methods to generate the models in a completely automatic fashion. Models of higher accuracy can be produced if homology modeling, based on the rhodopsin X-ray template, is supplemented by experimental structural constraints appropriate for the active orinactive receptor conformations, together with receptor-specific and ligand-specific interactions. The experimental constraints can be derived from mutagenesis and cross-linking studies, correlative replacements of ligand and receptor groups, and incorporation of metal binding sites between residues of receptors or receptors and ligands. This review focuses on the analysis of similarity and differences of the refined homology models of μ, δ, and κ-opioid receptors in active and inactive states, emphasizing the molecular details of interaction of the receptors with some representative peptide and nonpeptide ligands, underlying the multiple modes of binding of small opiates, and the differences in binding modes of agonists and antagonists, and of peptides and alkaloids.

Authors and Affiliations

Irina D. Pogozheva, Magdalena J. Przydzial, Henry I. Mosberg

Keywords

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The online version of this article (doi:10.1208/s12248-012-9350-9) contains supplementary material, which is available to authorized users.

EP ID EP681874
DOI 10.1208/aapsj070243
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