Study of the penetration of ionic liquids with active pharmaceutical ingredient into cell membranes by molecular dynamics simulation

• Grant number: 23/15437-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: February 01, 2024
• End date: January 31, 2026
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Physical-Chemistry
• Principal Investigator: Kalil Bernardino
• Grantee: Leticia Rafaella Dias
• Host Institution: Centro de Ciências Exatas e de Tecnologia (CCET). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil

Abstract

Topical medications are less severe to the digestive system, but the vast majority of active pharmacological ingredients present a challenge the difficulty in penetrating through the epidermis, since to do so they must present both good water solubility and affinity with the hydrophobic interior of lipid bilayers. An alternative that has attracted attention to facilitate the penetration of potential drugs through the epidermis consists of converting the drug into a cation or anion of an ionic liquid. Such modification also improves their solubility in water and eliminates problems associated with crystallization. In this work, we will use classical molecular dynamics simulations to compare the penetration of the anti-inflammatory ibuprofen in its neutral form into POPC lipid bilayers with the penetration of the deprotonated (anionic) form as biocompatible ionic liquids. As model systems, we will study biocompatible ionic liquids with the cations choline and decyl-choline, the second of which should display greater interaction with the hydrophobic portion of the bilayers compared to the first due to the additional alkyl group. The conversion of ibuprofen into the ibuprofenate anion should eliminate the problem of low water solubility of the neutral form, but at the same time, it should make its penetration through the hydrophobic core of the membrane difficult. We expect to observe a significant effect of the chosen cation, being expected that the decyl-choline cation will be incorporated into the membrane and thus facilitate the penetration of the anion. The effect of drug concentration will be evaluated by simulations of both the neutral form and the two ionic liquids in concentrated and diluted solutions. Based on the trajectories produced by the simulations, we will not only be able to evaluate the penetration of the drug into the membrane but also verify the effects that its incorporation and the cation in the ionic liquid induce on the structure and dynamics of the bilayer. This study should help in understanding the interaction of drugs with biological membranes and assist in the development of new formulations for topical use that provide better penetration through the epidermis. In addition to scientific gains, such a project must contribute to the student's academic training both through learning methodologies related to computational chemistry and through experience in a research group and application of the scientific method in developing the project.