Abstract
α-Mangostin (MGS) exhibits various pharmacological activities, including antioxidant, anticancer, antibacterial, and anti-inflammatory properties. However, its low water solubility is the major obstacle for its use in pharmaceutical applications. To increase the water solubility of MGS, complex formation with beta-cyclodextrins (βCDs), particularly with the native βCD and/or its derivative 2,6-dimethyl-β-CD (DMβCD) is a promising technique. Although there have been several reports on the adsorption of βCDs on the lipid bilayer, the release of the MGS/βCDs inclusion complex through the biological membrane remains unclear. In this present study, the release the MGS from the two different βCDs (βCD and DMβCD) across the lipid bilayer was investigated. Firstly, the adsorption of the free MGS, free βCDs, and inclusion complex formation was studied by conventional molecular dynamics simulation. The MGS in complex with those two βCDs was able to spontaneously release free MGS into the inner membrane. However, both MGS and DMβCD molecules potentially permeated into the deeper region of the interior membrane, whereas βCD only adsorbed at the outer membrane surface. The interaction between secondary rim of βCD and the 1-palmitoeyl-2-oleoyl-glycero-3-phosphocholine (POPC) phosphate groups showed the highest number of hydrogen bonds (up to 14) corresponding to the favorable location of βCD on the POPC membrane. Additionally, the findings suggested that electrostatic energy was the main driving force for βCD adsorption on the POPC membrane, while van der Waals interactions played a predominant role in DMβCD adsorption. The release profile of MGS from the βCDs pocket across the lipid bilayer exhibited two energy minima along the reaction coordinate associated with the permeation of the MGS molecule into the deeper region of the POPC membrane.
Highlights
Alpha-mangostin (MGS; Figure 1a) is a major component of xanthones extracted from pericarps or fruit hulls of mangosteen (Garcinia Mangostana L.) [1,2], and exhibits a wide range of pharmacological properties [3,4], including antibacterial [5], antioxidant [6], anti-inflammatory [7,8], and anticancer activities [9,10,11]
To investigate the permeability of free MGS, free βCDs, and MGS/βCDs inclusion complexes across the POPC membrane, triplicate Molecular Dynamics (MD) simulations were performed under the NP(z)AT ensemble across the POPC membrane, triplicate MD simulations were performed under the NP(z)AT ensemble for 500 ns, where the MD results are given in Figure S1 (SI) and Figures 2–4
These simulations that the A-ring of free MGS in both forms (A- and C-MGS) firstly dipped into the POPC membrane, showed that the A‐ring of free MGS in both forms (A‐ and C‐MGS) firstly dipped into the POPC
Summary
Alpha-mangostin (MGS; Figure 1a) is a major component of xanthones extracted from pericarps or fruit hulls of mangosteen (Garcinia Mangostana L.) [1,2], and exhibits a wide range of pharmacological properties [3,4], including antibacterial [5], antioxidant [6], anti-inflammatory [7,8], and anticancer activities [9,10,11]. There are several methods to improve the water solubility of the lipophilic MGS molecule and to enhance the compound penetration through the biological membrane. One such powerful technique is the modification of the native MGS molecule with some functional groups, such as amines and triazoles, which leads to an amphiphilic. MGS with an increased solubility [14,15] Another approach is the construction of complex formation with cyclodextrins (CDs), which is a commonly used method to promote the water solubility of numerous hydrophobic molecules [16,17,18]. That the truncated cone shape structure of CDs gives the potential to encapsulate small hydrophobic molecules and improve their stability and biological activity [16,19]
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