Determination of the structural requirements of μ-Opioid receptor ligands with docking

The μ-opioid receptor (MOR) is an important target in the search of novel analgesics. The MOR agonists, such as morphine, remain the most powerful analgesics available to relieve postoperative and cancer pains. However, these compounds produce adverse effects, including development of tolerance and physical dependence, sedation, constipation, some respiratory depression, nausea, and vomiting. These unwanted effects significantly diminish the patients’ quality of life. Thus, structural requirements of binding to this receptor attract considerable scientific attention. Different classes of compounds were synthesized and biologically tested as ligands of the receptor with different effects. The aim of the present study is to determine the structural requirements of the ligands with the help of docking and subsequent analysis. Ligand preparation was done with Avogadro software. Docking was performed with GOLD 5.2 using all functions available in the program. In vivo biological effects of the compounds were previously tested and already published. Binding to the receptor of four groups of compounds (arginine, kyotorphin, Melanocyte-inhibiting factor - 1 and Tyr-MIF-1 analogues) was analyzed and specific binding sites were determined. The main finding according to the results of docking and in vivo tests was the presence of a relationship between the size of the molecule and the presence of specific functional groups capable of binding the receptor stronger. Smaller molecules could enter the binding site of the receptor easily and could form the ligand-receptor complex with lower energy, which is associated with stronger and prolonged effect. Docking and subsequent mathematical analysis could be promising tools in the design of new and potent ligands of μ-opioid receptors.