Molecular dynamics and DFT analysis of artemisinin solubility in acidic deep eutectic solvents: Implications for cancer drug delivery

This study employs molecular dynamic simulations (MD) and density functional theory (DFT) to investigate the solubility of artemisinin (ART) in three acidic deep eutectic solvents (DES): Choline chloride (ChCl) combined with tartaric acid (TA), ascorbic acid (AA), and malonic acid (MA), in comparison to water. The results demonstrate a significant enhancement in the solubility of ART within the DES systems, particularly in ChCl/TA, where self-aggregation is notably absent, contrasting sharply with the aggregation observed in water. The dynamics of hydrogen bonding exhibit strong interactions between ART and AA, whereas interactions in ChCl/TA are minimal. DFT calculations indicate a decrease in the energy band gap of ART in the following order: water> ChCl/AA> ChCl/MA > ChCl/TA. This trend correlates with an increase in drug reactivity and its solvation energy. Additionally, the study explores ART's interactions with cancer cell membranes, revealing significant penetration into the membranes in the presence of ChCl/MA and ChCl/TA, while ART remains predominantly at the interface in both water and ChCl/AA. Structural analyses demonstrate that ART significantly affects the average area per lipid and membrane thickness in the DES solvents, with the most pronounced alterations observed in the ChCl/TA system. These findings underscore the critical role of solvent composition in mediating interactions between ART and the lipid bilayer, suggesting that deep eutectic solvents can enhance drug delivery and improve therapeutic efficacy in cancer treatment.