MOLECULAR DYNAMICS CONFORMATION OF OPIOID PEPTIDES

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Summary of Work: Molecular modeling comprised of molecular dynamics, conformational searching and superimpositions with crystal structures were used to propose a delta-opioid antagonist pharmacophore based on two sources: (1) the constrained and weakly bioactive cyclo(Dmt-Tic) and (2) the crystalline structure of N,N-dimethyl-Dmt-Tic-OH. In fact, the model of H-Dmt-Tic-OH and cyclo(Dmt-Tic) overlapped with the coordinates of the crystalline peptide with 0.6 and 03 rms, respectively; rms values under 1.0 indicate very close correlation in conformation. Characteristics of the 3-D structure are a cis peptide bond, gauche+ orientation of the Tic side chain, a near parallel orientat and close proximity of the aromatic rings. In fact, the ring distance of 5.4 angstroms appears to a common feacture of delta-opioid antagonists and differs from the more extended distances of aromatic rings (11-12 angstroms) found for delta and mu agonists. Based on the physicochemical data and further 2D 1H NMR involving temperature and solvent variation with di-, tri- and heptapeptide analogues will confirm these observations in spite of the inherent flexibility of the longer peptides. The data readily confirm the notion that peptide conformation exists in solution and is a required feature for recognition with high affinity by opioid receptor sites. New opioid di- and pentapeptide antagonists were developed based on the proposed pharmacophore for a delta-opioid agonist; for example, Dmt-D-Phe di- and pentapeptide analogues revealed that these compounds were mu-receptor antagonists. Molecualr modeling studies are continuing to delineate the differences between delta and mu antagonists and how their structure is compatible with that of the proposed receptor binding sites. Furthermore, with the availability of many more small peptide analogues with dual receptor binding characteristics or selective for the mu opioid receptor will assis in using molecular modeling in a predictive mode. The data will be used to develop delta- and mu-opioid antagonist pharmacophore which will serve as a scaffold for further design of highly potent ligands. The availability of mu-opioid antagonists would be compatible in drug treatment against cocain, heroine and morphine addiction.