Computer modeling applications utilized molecular dynamics conformational analyses of opioid peptides. Visualization of peptide conformation permits inferences to be drawn on changes in the dihedrals in the backbone, chirality and side-chain of the constituent residues that have direct impact on the binding proclivities of opioids. Knowledge gained from understanding the mechanisms of these interactions are essential for a rational approach to designing new peptides with agonist or antagonist activity. Computer modeling used various molecular dynamics programs, such as MacroModel, Spartan, AMBER, MULTI, and BioSym operating on a Silicon Graphics Indigo2. Molecular conformation on the opioid dipeptide revealed that the cluster of lowest energy conformers exhibited parallelism between the aromatic rings of Dmt and Tic. A comparable structure was observed for the lowest energy cluster of a diketopiperazine, cyclo(Dmt-Tic), which represents a new class of opioid peptides without a charged functionality that interact specifically with the d receptor. However, since this conformation was analogous to the crystal structure of c(Tyr-Tic), a compound whose receptor affinity is 3.5 borders of magnitude less, suggests that even though compounds may attain comparable low energy states, that does not indicate a similarity in the bioactive conformations. These data proposed a three-point attachment hypotheses as for the minimum requirements necessary for binding an opioid antagonist to a receptor: (i) hydrophobic p-p interactions between peptide and receptor residues; (ii) H-bond between tyramine OH and charge residue in receptor; and (iii) cation-p interactions involving a receptor cation and aromatic rings of ligand.
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