Solubility and solvation free energy of a cardiovascular drug, LASSBio-294, in ionic liquids: A computational study

To understand the solvation mechanism, we carried out molecular dynamics simulation of the cardiovascular drug, IASSBio-294, in water and seven ionic liquids (ILs): 1-ethyl-3-methylimidazolium methyl phosphonate ([EMIm][MPC, 1-ethyl-3-methylimidazolium ethyl phosphonate ([EMIm][EPn]), 1-ethy1-3-methylimidazolium acetate ([EMIm][Ac]), 1-butyl-3-methylimidazolium acetate ([BMIm][Ac]), 1,3-dimethylimidazolium methyl phosphonate ([DMIm][MPn]), 1-ethyl-3-methylimidazolium glycinate( [EMIm] [Gly]), Ethylammonium acetate ([EA][Ac]). We calculated the solvation free energy and relative solubility of the drug with reference to pure water. Coulombic and van der Waals contributions to the solvation free energy were computed to describe the solvation mechanism quantitatively. Atom-atom radial distribution functions (RDFs) were calculated to observe the possible interactions present between the drug molecule and ions of the ionic liquid. Due to the presence of aromatic rings, the stacking interaction is important for the solubility of the current drug molecule in ionic liquids. Therefore, stacking angle distributions were calculated to quantify the pi-pi interactions of imidazolium cations of ILs with the aromatic rings of the drug molecule. RDFs of alkyl chain carbons of the IL ions around the center of mass of aromatic rings were calculated to verify the contribution of van der Waals interactions. Comparing contributions of cations and anions towards the solvation free energy revealed that the hydrogen bonding between anions with the acidic hydrogens of the drug, and acidic hydrogen atoms of the cation with the carbonyl oxygen of the drug contribute to the Coulombic part of the solvation free energy. Moreover, the stacking of imidazolium cations and van der Waals interactions of alkyl chain hydrogens with the drug molecule contribute to the van der Waals contribution to the solvation free energy. Comparison of the experimental solubility with the calculated solvation free energy shows that the van der Waals interactions play a major role in solubilizing the drug molecule. (C) 2020 Elsevier B.V. All rights reserved.