Molecular Modeling Study On Endomorphin Analogs And The Heterodimerization Between Mu And Delta Opioid Receptors

Endomorphin have a strong antinociceptive effect on acute pain, similar to that of morphine. They are also more effective than the majority of the opioid peptides against neuropathic pain even at low doses, opening the possibility of using the two peptides as drugs. The molecular docking of a series of endomorphin analog with the mu opioid receptor was performed. The successive molecular dynamics of several proposed ligand-receptor complexes inserted into the phospholipid bilayer were carried out to optimize the complex and explore the conformational changes. Meaningful differences of their binding modes were detected and the involvement of some essential residues in ligand binding was also identified. Our proposed ligand-receptor model is in good agreement with previous site-directed mutagenesis experiments.A growing body of evidence indicated that the G protein coupled receptors exist as homo-or heterodimers in the living cell. The heterodimerization between mu and delta opioid receptors has attracted researchers'particular interests, it is reported to display novel pharmacological and signalling regulation properties. In our study, we construct the full-length 3D-model of mu and d elta opioid receptors using the homology modelling method. Threading program was used to predict the possible templates for the N-and C-terminus domains. Then, a 30 ns molecular dynamics simulations was performed with each receptor embedded in an explicit membrane-water environment to refine and explore the conformational space. Based on the structures extracted from the molecular dynamics, the likely interface of mu-delta heterodimer was investigated through the analysis of protein-protein docking, cluster, shape complementary and interaction energy. The computational modelling works revealed that the most likely interface of heterodimer was formed between the transmembranel,7 (TM1,7) domains of mu receptor and the TM(4,5) domains of delta receptor, with emphasis on mu-TMl and delta-TM4, the next likely interface was mu(TM6,7)-delta(TM4,5), with emphasis on mu-TM6 and delta-TM4. Our results were consistent with previous reports.