Molecular mechanisms of fentanyl mediated ?-arrestin biased signaling.

ABSTRACT: The development of novel analgesics with improved safety profiles to combat the opioid epidemic represents a central question to G protein coupled receptor structural biology and pharmacology: What chemical features dictate G protein or ?-arrestin signaling? Here we use adaptively biased molecular dynamics simulations to determine how fentanyl, a potent ?-arrestin biased agonist, binds the ?-opioid receptor (?OR). The resulting fentanyl-bound pose provides rational insight into a wealth of historical structure-activity-relationship on its chemical scaffold. Following an in-silico derived hypothesis we found that fentanyl and the synthetic opioid peptide DAMGO require M153 to induce ?-arrestin coupling, while M153 was dispensable for G protein coupling. We propose and validate an activation mechanism where the n-aniline ring of fentanyl mediates ?OR ?-arrestin through a novel M153 "microswitch" by synthesizing fentanyl-based derivatives that exhibit complete, clinically desirable, G protein biased coupling. Together, these results provide molecular insight into fentanyl mediated ?-arrestin biased signaling and a rational framework for further optimization of fentanyl-based analgesics with improved safety profiles.

SUBMITTER: de Waal PW 

PROVIDER: S-EPMC7176292 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature