Computational studies of opioid peptides and their receptor complexes.

摘要

It has now been over two decades since the identification of G-protein coupled receptors (GPCRs) and the endogenous ligands. With more than 50% of the drugs in the market aimed towards GPCRs, this area of research has become extremely important, as the mechanism of action of ligand binding as well as activation of the receptor are still debatable. Numerous efforts have been made to modify the endogenous as well as synthetic ligands in order to obtain better specificity and selectivity at the receptor. Also, since the only crystal structure of a GPCR available is that of the inactive state of rhodopsin, a number of three dimensional models of other GPCRs have been put forth based on homology modeling with rhodopsin and mutagenesis studies. Efforts have been made to predict the various steps from ligand binding to activation. Here, we have modeled the opioid receptors and their ligands in a complex using molecular dynamics simulations and used the models of the receptors to rationalize many of the mutation studies performed on them. Further, we have also suggested a plausible explanation for the differences between the known opioid agonists and antagonists, as well as the differences observed in the receptor subtypes. In addition, a series of molecular dynamics simulations have been performed in an effort to determine the biologically important pharmacophore groups (aromatic ring arrangement) in the bioactive form for delta-opioid receptor selective peptides. Finally, a docking study was also performed to determine the bioactive conformation of the delta opioid receptor binding ligands.