In silico studies of the interactions between propofol and fentanyl using Gaussian accelerated molecular dynamics

Abstract

Fentanyl is a potent opioid analgesic, which for decades has been used routinely in surgical and therapeutic applications. In addition to its analgesic properties, fentanyl also possesses anesthetic properties, which are not well understood. Fentanyl is used in the general anesthesia process to induce and maintain anesthesia in combination with the general anesthetic propofol, which fentanyl is known to potentiate. As the atomic-level mechanism behind the potentiation of propofol is unclear, we have used classical molecular dynamics simulations to study the interactions of these drugs with the Gloeobacter violaceus ion channel (GLIC). This ion channel has been identified as a target for many anesthetic drugs. We identified multiple binding sites using flooding style and Gaussian accelerated molecular dynamics (GaMD) simulations, showing fentanyl acting as a stabiliser that holds propofol within binding sites. Our extensive GaMD simulations were also able to show the pathway by which propofol blocks the channel pore, which has previously been suggested as a mechanism for ion channel modulation. General anesthesia is a multi-drug process and this study provides the first insight into the interactions between two different drugs in the anesthesia process in a relevant biological environment.

Communicated by Ramaswamy H. Sarma

Keywords:

• Ion channel
• molecular dynamics simulation
• enhanced sampling
• anesthetic
• opioid

Acknowledgements

This research was undertaken using the Supercomputing Facilities at Cardiff University operated by ARCCA on behalf of CSF and Supercomputing Wales. This equipment is part-funded by the Welsh European Funding Office (WEFO) as well as by Cardiff University. Information on the data underpinning the results presented here, including how to access them, can be found in the Cardiff University data catalogue at http://doi.org/10.17035/d.2020.0106797733

Disclosure statement

There are no conflicts to declare

Additional information

Funding

We acknowledge the Engineering and Physical Sciences Research Council (Grant No. EP/R512503/1) and AWE for funding.