Programme

P.99 -- Poster, VCTP-44

Date: Thursday, 1 August 2019

Time: 08:30 - 10:00

Molecular study of interactions of mu-opioid receptor in binding with biased and unbiased ligands by molecular dynamic simulation

Tran Ky Thanh (1), and Toan T. Nguyen (2)

(1) VNU Vietnam Japan University, 01 Luu Huu Phuoc street, Nam Tu Liem, Hanoi; (2) VNU Key Laboratory on Multiscale Simulation of Complex Systems, VNU University of Science, 334 Nguyen Trai street, Thanh Xuan, Hanoi

Mu-opioid receptors (µOR), members of G-protein coupled receptor (GPCR) family, are the main target of many opioid painkillers. As a biased ligand of µOR, TRV130 is a new promising pain relief drug due to its higher analgesic and reduced side effects. In this work, to elucidate the mechanism of biased signaling activation of TRV130, molecular dynamics (MD) simulation of two systems of µOR, each in its binding state with morphine (unbiased ligand) and TRV130 (biased ligand) was carried out. The results show that because of distinct interactions with the two ligands, µORs adopt two different conformations. The conformations of transmembrane 6 (TM6) and TM7 of µOR-morphine complex and µOR-TRV130 complex are significantly different in direction, fluctuation, and secondary structure. We suggest that the hydrophobic interaction between TRV130 with residue TRP293 (TM6) and TYR326 (TM7) which stabilizes TM6 and TM7 is one of the key factors leading to biased signaling. This result also suggests that the conserved proline and glycine residues play an important role in creating various states of GPCRs. In addition, the hydrophobic property of TRV130 leads to fewer hydrogen bonds with µOR than morphine; however, binding energy calculated with MM-PBSA method showed that the affinity of TRV130 toward µOR is higher than that of morphine. Consequently, hydrogen bond may not contribute much to affinity between ligands and µOR. For the next step – designing biased ligands, our results suggest that much attention should be paid to hydrophobic ligands which can create hydrophobic interaction with TRP293 and TYR326. Keywords: GPCR, mu-opioid receptor, biased signaling, MD simulation, morphine, TRV130

Presenter: Tran Ky Thanh