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  3. Evaluating solubility, stability, and inclusion complexation of oxyresveratrol with various β-cyclodextrin derivatives using advanced computational techniques and experimental validation

Evaluating solubility, stability, and inclusion complexation of oxyresveratrol with various β-cyclodextrin derivatives using advanced computational techniques and experimental validation

  • Comput Biol Chem. 2024 Jun 1:112:108111. doi: 10.1016/j.compbiolchem.2024.108111.
Saba Ali 1,  Aamir Aman 2,  Kowit Hengphasatporn 3,  Lipika Oopkaew 1,  Bunyaporn Todee 4,  Ryo Fujiki 3,  Ryuhei Harada 3,  Yasuteru Shigeta 3,  Kuakarun Krusong 1,  Kiattawee Choowongkomon 5,  Warinthorn Chavasiri 6,  Peter Wolschann 7,  Panupong Mahalapbutr 8,  Thanyada Rungrotmongkol 9
Affiliations

Affiliations

  • 1 Center of Excellence in Structural and Computational Biology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
  • 2 Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand.
  • 3 Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan.
  • 4 Department of Chemistry, Faculty of Science, Mahidol University, Rama VI Rd, Bangkok 10400, Thailand.
  • 5 Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand.
  • 6 Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand.
  • 7 Institute of Theoretical Chemistry, University of Vienna, Vienna 1090, Austria.
  • 8 Department of Biochemistry, Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand. Electronic address: panupma@kku.ac.th.
  • 9 Center of Excellence in Structural and Computational Biology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand; Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand. Electronic address: thanyada.r@chula.ac.th.
PMID: 38879954 DOI: 10.1016/j.compbiolchem.2024.108111
Abstract

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). 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 (AL 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.

Keywords

Inclusion complexes; Oxyresveratrol; Solubility enhancement, anti-cancer activity, classical MD, LB-PaCS-MD; β-cyclodextrin derivatives.

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