Comparative Interaction Studies of Quercetin with 2-Hydroxyl-propyl-β-cyclodextrin and 2,6-Methylated-β-cyclodextrin

• DOI: 10.5281/zenodo.6967423
• Publication Date: 2022-08-26
• Authors: Vasiliki Vakali; Michail Papadourakis; Nikitas Georgiou; Nikoletta Zoupanou; Dimitrios A. Diam...; Uroš Javornik; Paraskevi Papakyr...; Janez Plavec; Georgia Valsami; Andreas G. Tzakos; Demeter Tzeli; Zoe Cournia; Thomas Mauromoust...
• Keywords: Cyclodextrins; Hydroxyl Radical; beta-Cyclodextrins; Organic chemistry; quercetin; 2-hydroxyl-propyl-β-cyclodextrin; 2,6-methylated cyclodextrin; molecular interactions; NMR spectroscopy; molecular dynamics; absolute free energy calculation; FEP; fluorescence spectroscopy; Density Functional Theory (DFT); 2-hydroxyl-propyl-β-cyclodextrin; Molecular Dynamics Simulation; 01 natural sciences; molecular dynamics; Article; quercetin; 0104 chemical sciences; 3. Good health; NMR spectroscopy; QD241-441; Solubility; Humans; Quercetin; 2,6-methylated cyclodextrin; molecular interactions

Quercetin (QUE) is a well-known natural product that can exert beneficial properties on human health. However, due to its low solubility its bioavailability is limited. In the present study, we examine whether its formulation with two cyclodextrins (CDs) may enhance its pharmacological profile. Comparative interaction studies of quercetin with 2-hydroxyl-propyl-β-cyclodextrin (2HP-β-CD) and 2,6-methylated cyclodextrin (2,6Me-β-CD) were performed using NMR spectroscopy, DFT calculations, and in silico molecular dynamics (MD) simulations. Using T1 relaxation experiments and 2D DOSY it was illustrated that both cyclodextrin vehicles can host quercetin. Quantum mechanical calculations showed the formation of hydrogen bonds between QUE with 2HP-β-CD and 2,6Μe-β-CD. Six hydrogen bonds are formed ranging between 2 to 2.8 Å with 2HP-β-CD and four hydrogen bonds within 2.8 Å with 2,6Μe-β-CD. Calculations of absolute binding free energies show that quercetin binds favorably to both 2,6Me-β-CD and 2HP-β-CD. MM/GBSA results show equally favorable binding of quercetin in the two CDs. Fluorescence spectroscopy shows moderate binding of quercetin in 2HP-β-CD (520 M−1) and 2,6Me-β-CD (770 M−1). Thus, we propose that both formulations (2HP-β-CD:quercetin, 2,6Me-β-CD:quercetin) could be further explored and exploited as small molecule carriers in biological studies.