2021 FDA Science Forum
Computational Prediction of the Kinetics and Pathways of Opioid Dissociation from Mu-opioid Receptor
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Contributing OfficeCenter for Drug Evaluation and Research
Abstract
Synthetic opioids are powerful painkillers but are also among the most abused drugs. Computational predictions and detailed molecular understanding of opioid receptor binding kinetics and mechanisms may help determine the appropriate naloxone dose needed to adequately compete at the receptor and reverse opioid overdose. Towards this goal, an advanced molecular simulation method called metadynamics was applied to study the dissociation pathways and kinetics of fentanyl and its derivatives from the mu-opioid receptor, which is the primary target of clinically relevant opioids. Large-scale metadynamics simulations were performed to retrospectively predict the dissociation times of fentanyl, carfentanil and remifentanil. Remarkably, the simulations uncovered two types of unbinding mechanisms, one of which involves a new binding pocket, located deep in the receptor and below the well-known orthosteric site. The results of the study, together with the available X-ray crystal structures of the mu-opioid receptor, suggest that deep pocket binding is a major contributor to the long residence time and high binding affinity of fentanyl and its structural analogs. The developed protocol will be used to prospectively predict relative dissociation times of newly identified fentanyl analogs that continue to emerge from the dark market and determine the appropriate naloxone dose to reduce opioid-overdose mortality.
