Molecular dynamics simulation of interaction between selective serotonin reuptake inhibitors (SSRIs) and lipid bilayers

Abstract

Selective Serotonin Reuptake Inhibitors nowadays are the most commonly prescribed as powerful antidepressants, which have been commercially available for years, although the underlying mechanism is unclear, and the drug-profiles are not fully understood yet. Specifically, the missing of thermodynamic profiles in both sertraline and paroxetine, two common SSRIs antidepressants, in partitioning into brain membrane due to the limit in non-invasive methods constrain further development and optimization. In this study, the partitioning of the two represative SSRIs, sertraline and paroxetine, into the 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) lipid bilayers was simulated in three different temperatures from high to low using the molecular dynamics program. The changes in Gibbs free energy (ΔG), enthalpy (ΔH), entropy (ΔS) and orientation of these two drugs when transferring from the water phase into the lipid bilayer were determined. The result suggests that the interactions between two drugs and the DOPC bilayer are favorable at both the hydrophobic tails and the phosphate headgroup of DOPC lipid bilayers. The switching in points of interest when two drugs partitioning into bilayer are depending on the condition of temperature. While the sertraline partitioning trend was proved to be more energetically favorable at higher temperature than in lower one, paroxetine trend was unclear due to the effect of temperature on orientation value of the drugs. This could possibly be explained by the variation in hydration degree due to unsuitable force and inadequate time that lead to local minima. Moreover, complicated triple interaction between headgroup, water, and drug molecule also affected the measuring of ΔG. The decomposition of Gibbs free energy to enthalpy and entropy combine with the orientation values also prove the considerable influences of the temperature to the orientation profile of drug through hydration degree and local minima. Therefore, error in measuring ΔG occur and requires further studies to overcome these problems. Keywords: Molecular dynamics; Lipid bilayer; Antidepressant