Computational Structural Analysis of OPRD1-ORPM1 Hetero-Dimer Ligands and their Binding Pocket

Research into the pharmacological properties of G protein-coupled receptors (GPCRs) has highlighted the role of oligomerization in ligand binding and downstream signal transduction. The δ-μ opioid receptor hetero-dimer is an excellent example, with the potential for developing safer painkillers. This study explored the chemical properties and binding characteristics of ligands for the δ-μ opioid receptor hetero-dimer, δ-opioid receptor (OPRD1), and μ-opioid receptor (OPRM1) through computational structural analysis, which classified these ligands into three groups (Groups 1-3). Hetero-dimer ligands mainly clustered in Group 1, with low molecular weights, few rotatable bonds, low TopoPSA values, few ring structures, and high SLogP values—traits indicating high drug-likeness. Ligands in Groups 1 and 2 interacted with the TM2-TM3 Pocket of the receptor, while Group 3 did not. Docking simulations revealed that D1-M1-HLs from Groups 1 and 2 bind near the TM2-TM3 Pocket in either the active or inactive forms of OPRM1, suggesting that they bind to both receptor states. The interaction with the TM2-TM3 Pocket is crucial in linking ligand properties to binding modes. Group 1 D1-M1-HLs, including CYM51010, may exert specific effects through this binding, offering guidelines for designing new analgesics with fewer side effects.