Delivery of Alpha-Mangostin Using Cyclodextrins through a Biological Membrane: Molecular Dynamics Simulation

&alpha
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 (&beta
CDs), particularly with the native &beta
CD and/or its derivative 2,6-dimethyl-&beta
CD (DM&beta
CD) is a promising technique. Although there have been several reports on the adsorption of &beta
CDs on the lipid bilayer, the release of the MGS/&beta
CDs inclusion complex through the biological membrane remains unclear. In this present study, the release the MGS from the two different &beta
CDs (&beta
CD and DM&beta
CD) across the lipid bilayer was investigated. Firstly, the adsorption of the free MGS, free &beta
CDs, and inclusion complex formation was studied by conventional molecular dynamics simulation. The MGS in complex with those two &beta
CDs was able to spontaneously release free MGS into the inner membrane. However, both MGS and DM&beta
CD molecules potentially permeated into the deeper region of the interior membrane, whereas &beta
CD only adsorbed at the outer membrane surface. The interaction between secondary rim of &beta
CD 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 &beta
CD on the POPC membrane. Additionally, the findings suggested that electrostatic energy was the main driving force for &beta
CD adsorption on the POPC membrane, while van der Waals interactions played a predominant role in DM&beta
CD adsorption. The release profile of MGS from the &beta
CDs 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.