Computer-aided receptor modelling of human opioid receptors: (Mu, Kappa & Delta).
Opioid receptors (OPRs) are important agents in the centeral nervous system (CNS) function. These receptors belong to ''G-Protein Coupled Receptors (GPCRs)'' which have structural similarity with the BACTERIORHODOPSIN (bR). Because of receptor location in the membrane, three dimensional (3D) structure of GPCRs are unknown. The Computer-Aided Receptor Modelling on the basis of amino acid sequence, accompanied by the experimental results is a useful method to understanding the structure and mechanism of these receptors. In this study we tried to modell three types of Human Opioid Receptors; Mu, Kappa and Delta. We applied several methods to predict secondary structure (such as Hydropathicity Plot) of opioid receptors and also determined the possible regions of transmembrane helices (TMHs). Results were confirmed by inclusion of other human GPCRs sequence in multiple alignment methods. Then similarity between these receptors and bR were calculated on the basis of parameters such as Mutation Matrix and Secondary Structure Scale. After calculation and refinment of geometric coordinates of atoms located in helices by computerized mutation method (on the basis of 3D structure of bR, as a template) these data were corrected and optimized using Molecular Mechanics Calculations (AMBER Force Field). We used Morphin, Naloxone, Ethylketazocine (EKC) and SKF-10047 as general/specific ligand for these receptors. We optimized conformation of ligands by Quantum Mechanical Semiemprical Calculations (MOPAC). In final step we tried to dock ligands into the receptor cavity with attention to Mutagenesis Data and Structure-Activity Relationships (SAR) information. Our results show that in Delat receptors 'ASP-96' in TMH-II is important to binding of agonists and antagonists. In Mu receptors charged amino acid residues in TMH-II (ASP-116), TMH-III (ASP-149) and TMH-VI (HIS-299) interact with agonists. In Kappa receptors TMH-VI (GLU-297) and TMH-II (ASP-106) play a major role in interaction with antagonists. All of the mentioned residues are located in or near the inner cavity of receptors. With attention to results we suggest that other sites of receptors (such as loops and terminals) may be interact with ligands.
modelling opioid receptors g-protein coupled receptors bacteriorhodopsin morphine