Conclusions

Medicinal Chemistry Group: Computational Chemistry

The development of highly potent biologically active opioid compounds arose from the inclusion of Dmt into the di- and tripeptide sequence of Dmt-Tic-Xaa sequence. The advent of this key modification facilitated structural studies due to the reduction of the rotatable bonds inherent in opioid peptides in an attempt to elucidate unique low energy conformations that may be biologically relevant1, in conjunction with 1H NMR studies and substantiated by X-ray diffraction analyses. These conformational search techniques provided evidence for the following investigative observations and served as a basis for the development of low-energy models.

"The ultimate goal of theoretical studies on opioid peptides [and their respective receptors] is to gain a deeper understanding of the parameters required for µ- vs. δ-opioid receptor activation, and to develop three-dimensional pharmacophores that are useful for the design of functional opioid agonists and antagonists. In addition, a receptor model is critical in order to build hypotheses about an unknown binding sites and determine specific interactions that may be involved in agonist and antagonist activities in the design new opioid compounds."-- Bryant et al., Biopolymers/Peptide Science, 2003, 71, 86-102.