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[Display omitted] • Complexation with cyclodextrins can improve the water solubility and stability of regorafenib. • The highest binding affinity was observed in regorafenib-SBEβCD complex. • Regorafenib-SBEβCD complex exhibited the best stability and solubility. Regorafenib (RG) is an FDA-approved antitumor drug, effective against gastrointestinal stromal tumor and metastatic colorectal cancer. However, the applicability is limited by its low water solubility. This study aimed to address this issue by exploring the potential of cyclodextrins (CDs) as a solution. Specifically, β-cyclodextrin (βCD), γ-cyclodextrin (γCD) and mannose-γ-cyclodextrin (MγCD) were already reported for their ability to enhance the solubility and stability of RG by encapsulating it within their molecular structure. The present study focused on more convenient βCD derivatives, including dimethyl-β-cyclodextrin (DMβCD), hydroxypropyl-β-cyclodextrin (HPβCD), and sulfobutylether-β-cyclodextrin (SBEβCD), and compared them with βCD, γCD, and MγCD to assess their capability to form inclusion complexes with RG. Through 200-ns molecular dynamics simulations, it was observed that RG can form inclusion complexes with all CDs, adopting two distinct orientations: pyridine group insertion (P-form) and chlorobenzotrifluoride group insertion (C-form). These complex formations were primarily driven by van der Waals interactions. Notably, SBEβCD exhibited the highest number of atom contacts with RG and displayed the lowest solvent accessibility within the hydrophobic cavity. These results were consistent with the highest binding affinity observed when assessed using SIE, MM/GBSA, and MM/PBSA methods. Experimental findings further supported the computational predictions, as SBEβCD demonstrated a stability constant of 640 M−1, surpassing that of βCD (240 M−1). Overall, this study highlights the potential of modified cyclodextrins, particularly SBEβCD, as effective molecular encapsulating agents for RG, enabling improved solubility and stability for this lipophilic drug. [ABSTRACT FROM AUTHOR]

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 (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. [Display omitted] • 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. • Enhancing solubility and anticancer activity of OXY , especially OXY/SBEβCD showed superior inhibitory impact on MCF-7 cells compared to OXY alone. [ABSTRACT FROM AUTHOR]

Baicalein, a flavone derived from Scutellaria baicalensis Georgi, exhibits potent anti-inflammatory, antiviral, and anticancer properties. Its derivative, known as 8-bromobaicalein (BB), has been found to have strong cytotoxic effect on MCF-7 human breast cancer cells. However, its limited solubility in water has hindered its potential for wider applications. To address this issue, we investigated the use of cyclodextrins specifically βCD, 2,6-di-O-methyl-β-cyclodextrin (DMβCD), and hydroxypropyl-β-cyclodextrin (HPβCD) to improve the solubility of BB through inclusion complexation. During 250 ns molecular dynamics simulations, it was found that BB can form inclusion complexes with all βCDs. These complexes exhibit two distinct orientations: chromone group insertion (C-form) and phenyl group insertion (P-form). The formation of these complexes is primarily driven by van der Waals interactions. DMβCD has the highest number of atom contacts with BB and the lowest solvent accessibility in the hydrophobic cavity. These results coincide with the highest binding affinity from the MM/GBSA-based free energy calculation method. Experimental phase solubility diagrams revealed a 1:1 stoichiometric ratio (A L type) between BB and βCDs, in which BB/DMβCD showed the highest stability. The formation of inclusion complexes was confirmed by differential scanning calorimetry and scanning electron microscope methods. Additionally, the BB/DMβCD inclusion complex demonstrated significantly higher anticancer activity against MCF-7 human breast cancer cells compared to BB alone. These findings underscore the potential of DMβCD for formulating BB in pharmaceutical and medical applications. [Display omitted] • Inclusion complexation with βCDs enhances the solubility and stability of 8-bromobaicalein. • SEM, DSC, and molecular docking confirm inclusion complexation between 8-bromobaicalein and βCDs. • 8-bromobaicalein-DMβCD complex exhibits higher anticancer activity than 8-bromobaicalein alone. • The 8-bromobaicalein-DMβCD complex demonstrated optimal binding affinity, solubility, stability, and cytotoxicity. [ABSTRACT FROM AUTHOR]