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

Christopher Faulkner,Nora H De Leeuw

doi:10.1021/acs.jpcb.1c05438

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.

Highlights

The discovery of opioid molecules, for example, morphine, that produce effects such as the desensitization to painful stimuli, which is thought to be caused by binding to, and modulation of, G-protein-coupled receptors, has contributed significantly to the advance of modern medicine and surgical procedures
This study has two main goals: First we wished to ascertain whether molecular dynamics (MD) simulations using the umbrella sampling method can accurately predict permeability coefficients for fentanyl and its analogues using simple bilayer models and second, we wished to determine if the phospholipid used in the model makes a difference to the permeability predictions and what lipid is most reliable for simulation of such systems
These opioid molecules are all hydrophobic to varying extents, but the potential of mean force (PMF) profiles show expected behavior for these types of drug molecules

Summary

INTRODUCTION

The discovery of opioid molecules, for example, morphine, that produce effects such as the desensitization to painful stimuli, which is thought to be caused by binding to, and modulation of, G-protein-coupled receptors, has contributed significantly to the advance of modern medicine and surgical procedures. Many experimental techniques have been developed to investigate this important property, such as cell-based CaCo-2 assay[12] and parallel artificial membrane permeability assay (PAMPA).[13] These methods are widely used in industry and academia to calculate the permeabilities of various types of compounds, but they provide no information on the biophysics of membrane permeation.[14] Various linear response models and mathematical models, such as the quantitative structure permeability relationship[15] and steady-state models,[16] have been developed to make predictions based on experimental test sets, but their predictive performance has been relatively poor, and atomistic details of the processes of permeation cannot be deduced.[17] To gain atomic-level insight into the passive permeation of fentanyl and its analogues (shown in Figure 1), we have employed atomistic molecular dynamics (MD) simulations in combination with an umbrella sampling technique and the weighted histogram analysis method (WHAM) to construct the potential of mean force (PMF) curves for the drug permeation. This study has two main goals: First we wished to ascertain whether MD simulations using the umbrella sampling method can accurately predict permeability coefficients for fentanyl and its analogues using simple bilayer models and second, we wished to determine if the phospholipid used in the model makes a difference to the permeability predictions and what lipid is most reliable for simulation of such systems

COMPUTATIONAL DETAILS

RESULTS AND DISCUSSION

CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES