Opioid Ligand Binding to Opioid Receptors: Insight and Implications for Peptide Design

摘要

The three opioid receptors (u, 8, and k) are important targets for pain management and have also shown promise as targets for treatment of addiction and mood disorders. In the past, research in the field commonly focused on analysis of structure-activity relationships (SAR) and ligands' conformational preferences. Recently, advancements permitted determination of crystal structures for each of the opioid receptors in their antagonist-bound states [1-5]. These structures, combined with computational approaches, permit examination of how opioid ligands may bind to opioid receptors at the atomic level, knowledge that would facilitate the design and development of opioid receptor modulators with greater therapeutic potential. [D-Pen~2,D-Pen~2]enkephalin (DPDPE, 1) (Figure 1) is a selective cyclic peptide agonist at the 8 opioid receptor. The SAR and conformational preferences of DPDPE and its analogs were the subject of prior investigation [6-9]. These studies showed that the stereochemistry of the third amino acid has a profound effect on the structure and 8 opioid receptor affinity of compounds in the series. This SAR makes DPDPE and its analogs particularly amenable to docking studies, which may help elucidate the active conformation of compounds possessing this scaffold. The macrocyclic tetrapeptide CJ-15,208 (2) and its analogs also have a constrained cyclic structure and bind to opioid receptors [10-12] even though they lack the canonical opioid pharmacophore. While this unusual structure confers many desirable drug-like properties-including oral bioavailability and blood-brain barrier permeability [13-15]-it makes docking studies and rational design of CJ-15,208 analogs particularly challenging. Herein we utilize docking studies to explore likely binding modes of DPDPE and its analogs, information that can then be used to predict possible binding modes of other opioid ligands, including macrocyclic tetrapeptides such as CJ-15,208.