Predicting the Membrane Permeability of Fentanyl and Its Analogues by Molecular Dynamics Simulations

[Image: see text] The lipid membrane is considered a crucial component of opioid general anesthesia. The main drug used for the induction and maintenance of opioid anesthesia is fentanyl and its various analogues. However, these drugs have different clinical effects, and detailed atomic-level insight into the drug–membrane interactions could lead to a better understanding how these drugs exert their anesthetic properties. In this study, we have used extensive umbrella sampling molecular dynamics simulations to study the permeation process of fentanyl and three of its analogues into a variety of simple phospholipid membrane models. Our simulations show that we can accurately predict the permeability coefficients of these drug molecules, which is an important process in understanding how pharmaceuticals reach their molecular targets. We were also able to show that one phospholipid provides more accurate predictions than other lipids commonly used in these types of permeation studies, which will aid future studies of these types of processes.