Atomistic insights into the intermolecular interactions of Cistanoside A from Cistanche deserticola with natural deep eutectic solvents

Natural Deep Eutectic Solvents (NADES) have emerged as sustainable alternatives to conventional solvents, offering enhanced solubility and biocompatibility for natural bioactive compounds. In this study, we employ density functional theory (DFT) calculations and classical all-atom molecular dynamics (MD) simulations to investigate the intermolecular interactions between Cistanoside A, a key bioactive component from Cistanche deserticola, and NADES. DFT calculations provide electronic insights into the complexation mechanism. The Highest occupied molecular orbital (HOMO)– Lowest unoccupied molecular orbital (LUMO) analysis demonstrates significant electronic redistribution upon complex formation, with a reduction in the HOMO-LUMO energy gap, indicating enhanced charge delocalization and increased chemical reactivity. These electronic changes suggest that NADES not only enhance intermolecular interactions but also influence the molecular properties of Cistanoside A, potentially improving its bioavailability. Classical all-atom MD simulations reveal strong hydrogen bonding and van der Waals interactions between Cistanoside A and NADES, contributing to the enhanced intermolecular interactions and stability of the complex. The analysis of hydrogen bonds indicates a structural reorganization within NADES upon interaction with Cistanoside A, confirming the NADES adaptability in forming a stable complex. Interaction energy calculations further support the favorable thermodynamics of complexation, highlighting the key role of NADES in improving intermolecular interaction with Cistanoside A. The combined DFT calculation and classical all-atom MD simulation insights offer a fundamental understanding of NADES-assisted bioavailability enhancement, paving the way for their application in pharmaceutical and biomedical formulations.