Novel synthetic opioids (NSOs), such as fentanyl and nitazene analogs, dominate the recreational drug market and are the main culprits for the opioid crisis. By taking advantage of the crystal structures of the µ-opioid receptor (MOR), we investigated the binding mechanisms of NSOs in terms of both the binding orientation and the ligand conformation. Specifically, we characterized the free energy landscape of fentanyl conformations with metadynamics simulations, as well as performed long-timescale molecular dynamics simulations to compare and evaluate several possible fentanyl binding conditions. Our results indicate that the most preferred binding pose in the MOR binding pocket corresponds well with the minima on the energy landscape of fentanyl in the absence of the receptor. The interactions between fentanyl and the MOR may stabilize a slightly unfavored fentanyl conformation in an alternative binding pose. By extending similar investigations to fentanyl and nitazene analogs, our findings establish a structure-activity relationship of NSOs binding at the MOR, which provides a structural basis to understand the potential toxicity of the emerging NSOs. In addition, we leverage such insights and the established MOR model framework to reveal different binding mechanisms of SR-17018 and brorphine, two analgesics sharing same chemical scaffold but likely possessing varied safety profiles.

The binding mechanisms of the abused synthetic opioids at the µ-opioid receptor shed light on developing safe analgesics

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.