Molecular dynamics simulation of nonsteroidal antiinflammatory drugs, naproxen and relafen, in a lipid bilayer membrane

Abstract

Naproxen and relafen, as nonsteroidal antiinflammatory drugs, were simulated in neutral and charged forms and their effects on a lipid bilayer membrane were investigated by molecular dynamics simulation using Groningen machine for chemical simulations software (GROMACS). Simulation of 10 systems was performed, which included different dosages of the drug molecules, naproxen and Relafen, in charged and neutral forms, and a mixture of naproxen and Relafen in neutral forms. The effects of the mixture and the individual drugs' dosages on membrane properties, such as electrostatic potential, order parameter, diffusion coefficients, and hydrogen bond formation, were analyzed. Hydration of the drugs in the membrane system was investigated using radial distribution function analysis. Using fully hydrated dimyristoylphosphatidylcholine (DMPC) as a reference system, 128 lipid molecules and water molecules were simulated exclusively, and the same simulation technique was performed on 10 other systems, including drug mixtures and a DMPC membrane. Angular distributions of lipid chains of the membrane were calculated, and the effects of the drug insertion and chain orientation in the membrane were evaluated.

Shedding light on the puzzle of drug-membrane interactions: Experimental techniques and molecular dynamics simulations

“…One strategy is to use different concentrations of the drug or to even study the simultaneous effect of different drugs, as performed by [270]. They showed a dosage-dependent effect, and they concluded that drug mixtures have a larger effect even at a lower dosage compared to the dosage needed for a single drug [270].…”

“…Importantly, it should be noted that for some studies, a single drug molecule is used; hence, it is unlikely that meaningful perturbations in the membrane can be observed [304]. One strategy is to use different concentrations of the drug or to even study the simultaneous effect of different drugs, as performed by [270]. They showed a dosage-dependent effect, and they concluded that drug mixtures have a larger effect even at a lower dosage compared to the dosage needed for a single drug [270].…”

“…MD simulations can be used to study the formation of hydrogen bonds, which are determined by defining cutoffs for the acceptor-donor-hydrogen angle (e.g., angles O-H-O and O-H-N higher than 90°) and for the hydrogen-acceptor distances (e.g., less than 2.5 Å) [270,271].…”

Molecular dynamics simulations and free energy profile of Paracetamol in DPPC and DMPC lipid bilayers

“…Molecular dynamics simulations may provide valuable complementary to experiments information about details of interactions between the molecules. 3 ,14 However, despite enormous growth of the number of studies on computer simulations of lipid bilayers and utilizing GROMACS package for MD simulations (for example, see recent reviews, [15][16][17][18] ) there are no investigations on computer modelling of analgesics in lipid bilayers. Also the interaction between Paracetamol (acetaminophen) and two model membranes made of DPPC and dimyristoylphosphatidylcholine (DMPC) molecules in their liquid crystalline states has been probed.…”

The partition and transport behavior of cytotoxic ionic liquids (ILs) through the DPPC bilayer: Insights from molecular dynamics simulation

“…The electrostatic potential (EP) across the membrane is one of the most important properties of lipid bilayers that can affect the mechanism of a voltage-gated ion channel. One reason for the appearance of this potential is the orientation of water dipoles and lipid headgroup dipoles at the water-membrane interface (Mojumdar & Lyubartsev, 2010;Yousefpour et al, 2013). The EP can be influenced by the presence of ions and other charged components (H€ ogberg & Lyubartsev, 2008).…”