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

Abstract

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.

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…Pain medication Paracetamol [283][284][285] Pain medication, opioid receptors Morphine [132], Fentanyl [132], Fentanyl and its analogues [286], Codeine [287] Local anesthetics Benzocaine [288][289][290], KP-23 [147], Dibucaine [291], Lidocaine [289,292,293], Articaine [289], Tetracaine [294,295], Prilocaine [296], Dyclonine, Butamben [290] General anesthetic Xenon [124,125], Chloroform [292,[297][298][299][300][301], Halothane [146,298,302,303], Isoflurane [297,299,304,305], Phenyl-ethanol [306], Desflurane [305,307], Sevoflurane [305,308], Propofol [305,309,310], Diethyl ether [298,308], Enflurane…”

Recent advances on molecular dynamics-based techniques to address drug membrane permeability with atomistic detail

“…Indeed, atomistic details (e.g., formation of noncovalent interactions) and membrane complexity can be major constraints to the predictability and interpretability of such models when applied to unknown compounds. In fact, different types of bilayers have a diverse range of lipid tails, differing on chain lengths and saturation [17] . This variability influences the permeation of drugs in distinct regions of the cellular membrane.…”

Exploring the thermally-controlled fentanyl transdermal therapy to provide constant drug delivery by physics-based digital twins

“…As a future improvement, computational and mathematical methods could be employed to personalize and adapt transdermal therapy for patients while reducing clinical trial and error methods, which are costly and might put the patient’s health and well-being at risk. Some of these computational methods aim to monitor fentanyl penetration through the skin via molecular dynamics models (Faulkner and de Leeuw 2021; Otto and De Villiers 2013; Rim, Pinsky, and Van Osdol 2009), brick-and-mortar models (Naegel, Heisig, and Wittum 2013), or diffusion models (Anissimov et al 2013; Bahrami et al 2023; Bahrami, Rossi, and Defraeye 2022; Thijs Defraeye et al 2020; Thijs Defraeye, Bahrami, and Rossi 2021; Iordanskii et al 2000; Walicka and Iwanowska-Chomiak 2018). Additionally, other computational methods focus on the pharmacokinetics and pharmacodynamics model, which aim to predict the drug concentration in plasma by considering the metabolism and eliminations and, eventually, the drug’s effect corresponding to the drug concentration (Bahrami et al 2023; Bahrami, Rossi, and Defraeye 2022; Björkman 2003; Madden et al 2019; Pan and Duffull 2019).…”