MOLECULAR DYNAMICS CONFORMATION OF OPIOID PEPTIDES

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Summary of Work: Molecular modeling (molecular dynamics, conformational searching, superimpositions with crystal structures) were used to propose a d-opioid antagonist pharmacophore based on the constrained and bioactive cyclo(Dmt-Tic). Characteristics of the 3-D structure are a cis peptide bond, gauche+ orientation of the Tic side chain and close proximity of the aromatic rings. Based on the physicochemical properties for binding, new opioid dipeptide antagonists were developed. Efforts to propose a pharmacophore for a d-opioid agonist proved difficult due to the flexibility of these heptapeptides. One approach replaced residues in deltorphin with a-aminoisobutyric acid (Aib) or aminoacycloalkanes which induce helical secondary structure in peptides of 7-20 residues. MD simulations revealed that Aib induced changes in secondary structure of deltorphin when replacing D-Ala2 or Asp4, or D-Ala2-Phe3, but not Phe alone. This provided precedence for 2-D 1H NMR analyses of these derivatives and conformational changes were observed using COSY, NOESY, HOHAHA, ROESY and DQF-COSY experiments. Further 2D 1H NMR involving temperature and solvent variation will confirm these observations. The data will be used to develop a d-opioid agonist pharmacophore which will serve as a scaffold for further design of highly potent ligands.