Evaluating Solubility, Stability, and Inclusion Complexation of Oxyresveratrol with Various β-cyclodextrin Derivatives Using Advanced Computational Techniques and Experimental Validation

Oxyresveratrol (OXY), a natural stilbenoid in mulberry fruits, is known for its diverse pharmacological properties. However, its clinical use is hindered by low water solubility and limited bioavailability. In the present study, the inclusion complexes of OXY with β-cyclodextrin (βCD) and its three analogs, dimethyl-β-cyclodextrin (DMβCD), hydroxypropyl-β-cyclodextrin (HPβCD) and sulfobutylether-β-cyclodextrin (SBEβCD), were investigated using in silico and in vitro studies. Molecular docking revealed two binding orientations of OXY, namely, 4′,6′-dihydroxyphenyl (A-form) and 5,7-benzenediol ring (B-form).

Highlights

Investigation of inclusion complexes of OXY with βCD and analogs using in silico and in vitro studies.

Utilizing novel Parallel Cascade Selection Molecular Dynamics simulations for studying drug-cyclodextrin (CD) inclusion complexes, providing insights into binding orientations.

Enhancing solubility and anticancer activity of OXY after inclusion complexation, especially OXY/SBEβCD showed superior inhibitory impact on breast cancer cell line MCF-7 compared to OXY alone.

Molecular Dynamics simulations suggested the formation of inclusion complexes with βCDs through two distinct orientations, with OXY/SBEβCD exhibiting maximum atom contacts and the lowest solvent-exposed area in the hydrophobic cavity. These results corresponded well with the highest binding affinity observed in OXY/SBEβCD when assessed using the MM/GBSA method. Beyond traditional simulation methods, Ligand-binding Parallel Cascade Selection Molecular Dynamics method was employed to investigate how the drug enters and accommodates within the hydrophobic cavity. The in silico results aligned with stability constants: SBEβCD (2060 M^-1), HPβCD (1860 M^-1), DMβCD (1700 M^-1), and βCD (1420 M^-1).

All complexes exhibited a 1:1 binding mode (A_L type), with SBEβCD enhancing OXY solubility (25-fold). SEM micrographs, DSC thermograms, FT-IR and ¹H NMR spectra confirm the inclusion complex formation, revealing novel surface morphologies, distinctive thermal behaviors, and new peaks. Notably, the inhibitory impact on the proliferation of breast cancer cell lines, MCF-7, exhibited by inclusion complexes particularly OXY/DMβCD, OXY/HPβCD, and OXY/SBEβCD were markedly superior compared to that of OXY alone.

Materials

OXY was obtained from Dr. Warinthorn Chavasiri at the Department of Chemistry, Faculty of Science, Chulalongkorn University in Bangkok, Thailand. HPβCD (C63H112O42, 1541.5 g/mol) (DS, 4.5) and βCD (C42H70O35, 1134.56 g/mol) were obtained from FUJIFILM Wako Pure Chemicals Corporation in Osaka, Japan. SBEβCD (C46H79O38SNa, 2174.56 g/mol) (DS, 6.0-7.1) was purchased from Medchem Express (Monmouth Junction, NJ, USA). While DMβCD (C56H98O35, 1331.36 g/mol) was purchased from Sigma-Aldrich.

Saba Ali, Aamir Aman, Kowit Hengphasatporn, Lipika Oopkaew, Bunyaporn Todee, Ryo Fujiki, Ryuhei Harada, Yasuteru Shigeta, Kuakarun Krusong, Kiattawee Choowongkomon, Warinthorn Chavasiri, Peter Wolschann, Panupong Mahalapbutr, Thanyada Rungrotmongkol, Evaluating Solubility, Stability, and Inclusion Complexation of Oxyresveratrol with Various β-cyclodextrin Derivatives Using Advanced Computational Techniques and Experimental Validation, Computational Biology and Chemistry, 2024, 108111, ISSN 1476-9271, https://doi.org/10.1016/j.compbiolchem.2024.108111.

Evaluating Solubility, Stability, and Inclusion Complexation of Oxyresveratrol with Various β-cyclodextrin Derivatives Using Advanced Computational Techniques and Experimental Validation

Highlights

Materials

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