Kinetics and Mechanism of Fentanyl Dissociation from the μ-Opioid Receptor.

ABSTRACT: Driven by illicit fentanyl, opioid related deaths have reached the highest level in 2020. Currently, an opioid overdose is resuscitated by the use of naloxone, which competitively binds and antagonizes the μ-opioid receptor (mOR). Thus, knowledge of the residence times of opioids at mOR and the unbinding mechanisms is valuable for assessing the effectiveness of naloxone. In the present study, we calculate the fentanyl-mOR dissociation time and elucidate the mechanism by applying an enhanced sampling molecular dynamics (MD) technique. Two sets of metadynamics simulations with different initial structures were performed while accounting for the protonation state of the conserved H297^6.52, which has been suggested to modulate the ligand-mOR affinity and binding mode. Surprisingly,

SUBMITTER: Mahinthichaichan P 

PROVIDER: S-EPMC8715493 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature