Title:  Binding mechanism and dissociation kinetics of fentanyl and analogs at the mu-opioid receptor
Abstract:  The nation's opioid crisis has reached a new level. The overdose reversal agent naloxone antagonizes opioid through competitive binding at the mu-opioid receptor (mOR). Thus, knowledge of opioid's residence time is important in assessing naloxone's effectiveness. However, an X-ray structure of fentanyl or naloxone bound mOR is lacking. In this talk I will discuss our progress in understanding fentanyl-mOR binding and predicting the dissociation kinetics using advanced molecular dynamics simulations. Exploiting the microscopic insights, we then developed a machine learning model to predict how structure modification changes opioid's residence time. The proof-ofconcept approach may be used to inform effective naloxone dosing regimen, which is particularly needed in anticipation of new opioids emerging from the darknet market.