Computational screening of natural deep eutectic solvents for improving naringenin solubilization and membrane behavior in DMPC liposomes Using COSMO-RS and COSMOmic.

CONTEXT: Naringenin is a natural flavonoid compound with potential pharmaceutical use that is limited by its low aqueous solubility and bioavailability. In this work, we used an in silico drug delivery approach to screen natural deep eutectic solvents (NaDESs) that may improve solubility, membrane affinity, and predicted relative release of naringenin from 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes. Of all systems screened, betaine-based NaDESs were found to provide the best solubilization efficiency while choline chloride-caffeic acid provided the most stabilizing membrane affinity. Drug-membrane interactions characterized by free-energy, intermolecular interaction, and permeability calculations were shown to be dependent on the NaDES composition. In particular, a tunable relationship between hydrogen-bonding and van der Waals (vdW) interactions was shown to dictate encapsulation and Predicted relative release behavior allowing for rational computational selection of NaDESs to enhance liposomal delivery of poorly water-soluble drugs.

METHODS: Quantum chemical calculations were conducted based on density functional theory at M06/def2- TZVP level. Solubility, activity coefficients, intermolecular interactions and thermodynamics were predicted by COSMO-RS. Membrane partitioning, free-energy profiles, diffusion, permeability, and distribution in DMPC bilayers were assessed by COSMOmic.