Atomistic molecular dynamics (MD) and steered MD simulations in combination with umbrella sampling methodology were utilized to study the general anesthetic propofol and the opioid analgesic fentanyl and their interaction with lipid bilayers, which is not yet fully understood. These molecules were inserted into two different fully hydrated phospholipid bilayers, namely, dioleoylphosphatidylcholine (DOPC) and dipalmitoylphosphatidylcholine (DPPC), to investigate the effects that these drugs have on the bilayer. We determined the role of the lipid chain length and saturation on the behavior of the two drugs. Pure, fully hydrated DOPC and DPPC bilayers were also simulated, and the results were in excellent agreement with the experimental values. Various structural and mechanical properties of each system, such as the area per lipid, area compressibility modulus, order parameter, lateral lipid diffusion, hydrogen bonds, and radial distribution functions, have been calculated to assess how the drug molecules affect the different bilayers. From the calculated results, we show that fentanyl and propofol generally follow similar trends in each bilayer but adopt different favorable positions close to the headgroup/chain interface at the carbonyl groups. Propofol was shown to selectively form hydrogen bonds at the carbonyl carbon in each bilayer, whereas fentanyl interacts with water molecules at the headgroup interface. From the calculated free-energy profiles, we determined that both molecules show a preference for the low-density, low-order acyl chain region of the bilayers and both significantly preferred the DOPC bilayer with propofol and fentanyl having energy minima at −6.66 and −43.07 kcal mol–1, respectively. This study suggests that different chain lengths and levels of saturation directly affect the properties of these two important molecules, which are seen to work together to control anesthesia in surgical applications.
Fentanyl is an opioid analgesic, which is routinely used in general surgery to suppress the sensation of pain and as the analgesic component in the induction and maintenance of anesthesia. Fentanyl is also used as the main component to induce anesthesia and as a potentiator to the general anesthetic propofol. The mechanism by which fentanyl induces its anesthetic action is still unclear, and we have therefore employed fully atomistic molecular dynamics simulations to probe this process by simulating the interactions of fentanyl with the Gloeobacter violaceus ligand-gated ion channel (GLIC). In this paper, we identify multiple extracellular fentanyl binding sites, which are different from the transmembrane general anesthetic binding sites observed for propofol and other general anesthetics. Our simulations identify a novel fentanyl binding site within the GLIC that results in conformational changes that inhibit conduction through the channel.
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.
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.
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