The role of backbone conformation in deltorphin II binding: A QSAR study of new analogues modified in the 5-, 6-positions of the address domain Original Research Article

The δ selectivity of the opioid heptapeptides deltorphin I and II has been attributed to the C-terminal ‘address’ domain, the hydrophobic Val5–Val6 residues apparently playing a topographical role. We now report the synthesis, opioid binding affinities, and a QSAR study of a series of peptides in which one of the valine side chains was altered. QSAR analyses included previously published models for a binding pocket interaction and an optimum size (Schullery, S.; Mohammedshah, T.; Makhlouf, H.; Marks, E.; Wilenkin, B.; Escobar, S.; Mousigian, C.; Heyl, D. Bioorg. Med. Chem. 1997, 5, 2221), and a new approach for backbone conformational effects using Langevin dynamics simulation (PM3 semi-empirical force field) of an isolated peptide fragment containing the side chain and flanking peptide bonds. No evidence is found of binding pocket interactions or optimum size for either the position-5 or -6 side chain. Rather, δ binding is generally disfavored while μ binding is either unaffected (position-5) or favored (position-6) by larger side chains. The dynamics results provide evidence of similar ‘local’ conformation roles for the positions 5 and 6 side chains. Specifically, δ binding is favored by side chains that maximize the extension of the backbone, measured as the through-space distance between peptide fragment ends, the angle between lines connecting the α-carbon with fragment ends, or the difference between the psi and phi peptide angles.