Computational Pharmacodynamic Analysis of Cyclopeptides Derived from c[Trp-Phe-D-Pro-Phe] (CJ-15,208), an Unusual Class of Mixed μ/k-Opioid Receptor Ligands Lacking the Traditional Pharmacophores

<b>Background:</b> There is currently increasing interest in atypical opioid compounds capable of expanding their clinical applications beyond pain management, including the treatment of psychiatric disorders and substance abuse. In this context, the cyclotetrapeptide c[Trp-Phe-D-Pro-Phe] (CJ-15,208, <b>1</b>) and its derivatives represent an unusual class of opioid peptides. This compound was found to be a mixed KOR/MOR antagonist in vitro, but it acted as an agonist in vivo. For its diverse analogues, it appeared that receptors' affinity, selectivity, and agonist/antagonist activity greatly varied upon modifications to backbone geometry and the 3D display of pharmacophores. <b>Methods:</b> We utilized NMR, molecular dynamics, and molecular docking to analyze 3D structures and pharmacodynamic properties of selected representative cyclopeptide analogues of <b>1</b>. <b>Results:</b> The simulations support that, despite its contradictory functional activity in vitro and in vivo, <b>1</b> can bind to the active conformation of receptors in an agonist-like fashion. In general, Trp appeared to be the fundamental pharmacophore in the ligand-receptor complexes. In particular, agonists showed a direct interaction between the indole ring and the carboxylate of the conserved Asp(3:32). <b>Conclusions:</b> These studies support a distinctive pharmacodynamic model for this class of compounds, potentially useful for the design of opioid compounds with novel binding/activity profiles and improved therapeutic effects.