Biologia computacional e bioquímica quântica dos opioides: descrição comparativa das interações intermoleculares do Fentanil e da Morfina ligados ao receptor μ-opioide

Abstract

The μ-opioid receptor (μOR) is one of the four known subtypes of opioid receptors (μ, δ, κ, and NOP) and plays a fundamental role in signaling the analgesic effects of both endogenous and synthetic opioids. Clinically, the administration of opioids such as morphine (MOR) and fentanyl (FEN) aims to control pain in patients with chronic diseases, cancer, and other illnesses. However, these medications present serious side effects, such as respiratory depression and the risk of dependence, limiting their therapeutic use. Given this, this project aims to study, at the molecular level, using computational biology and quantum biochemistry tools, the mechanism and interaction energy of two major opioids, morphine and fentanyl, with μOR and, with this, provide information that may contribute to the development of new drugs that offer high analgesic efficiency with few side effects. To this end, the structures of the μOR::MOR and μOR::FEN complexes present in the crystals with PDB IDs 8EF6 and 8EF5, respectively, were prepared. Afterward, the complexes were inserted into a phospholipid bilayer (POPC). Subsequently, independent simulations of energy minimization, equilibrium, and molecular dynamics (MD) were performed in triplicate for the two systems using GROMACS. Finally, quantum biochemistry calculations were performed to quantify the interaction energies between the drugs and the receptor through Density Functional Theory (DFT). As a result, strong energetic interactions of the μOR residues with both ligands were identified, achieving interaction energy values of −74, 21; kcal · mol−1 (dynamics 3) and −69, 43; kcal · mol−1 (dynamics 1) for fentanyl and morphine, respectively. For morphine, critical residues were located in TM3 (MET153, ASP149, TYR150), TM6 (HIS299, ILE298, TYR328, VAL302), and TM7 (ILE324, TRP295). For fentanyl, the most interactive residues were found in TM3 (ASP149, MET153, ILE146, CYS142, TYR150), TM6 (ILE298, TRP295, HIS299), TM7 (ILE324, GLY327, TYR328, TRP320), TM5 (LYS235, VAL238), and TM2 (GLN126). Furthermore, the average interaction energy for morphine was −65,34 kcal · mol−1, and for fentanyl, it was −63,80 kcal · mol−1, suggesting that the former has a lower interaction energy with μOR. The results obtained in this work may contribute to the design of new drugs with greater specificity for μ-opioid receptors.