Opioids, such as morphine, fentanyl and codeine, are powerful and addictive pain relievers; overdose can result in sudden death. Understanding the opioid-receptor interactions and predicting unbinding kinetics may help design and develop preventive measures. Due to the long residence time, such processes cannot be currently described by unbiased molecular dynamics simulations. Here we make use of the metadynamics technique to probe the unbinding pathways and kinetics of fentanyl and its derivatives from the mu-opioid receptor, which is a member of the G-protein coupled receptor family. Based on an agonist-bound crystal structure and ligand docking, sets of metadynamics simulations are performed. The method expediates the dissociation by orders of magnitude, while recovering the unbiased dissociation times in the range comparable to experimental values. Furthermore, a new high-affinity ligand binding pocket located beneath the orthosteric binding site is identified, providing new insights into receptor desensitization and drug tolerance.

Fentanyl unbinding pathways and kinetics from a metadynamics study

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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