The FMO analysis of the molecular interaction of fentanyl derivatives with the μ-opioid receptor

Fentanyl is a synthetic opioid analgesic used as a pain reliever and an anaesthetic. Minor differences in the substituent on the N-phenylethyl or the N-phenylpropanamide groups may be a contributing factor in reducing or increasing the affinity of its derivatives. Recently, the Drug Enforcement Administration officially identified illicitly manufactured fentanyl as a threat. In this paper the use of molecular docking of the complexes between fentanyl analogues and the receptor model based on crystal structure of the mu-opioid receptor (5C1M) is described. The Fragment Molecular Orbital method (FMO) reveals an insight into the chemical nature of the ligand-receptor interaction. The ionic-electrostatic contacts between N-H and Asp147 (TM3) and those between His54 and the N-phenethyl group of ligand have stabilized interactions, while Lys233 (TM5) and Lys303 (TM6) have destabilized contacts. Furthermore, the predominant electrostatic term correlates with the total interaction energy. Correlations between the dispersion and exchange as well as the charge transfer and dispersion terms indicate that they can be used as descriptors to design ligand-receptor interactions of analogous derivatives.