Molecular dynamic simulations on inclusion complexes of alpha-mangostin with beta-cyclodextrin and derivatives in phospholipid bilayer

Abstract

Alpha-mangostin (MGS), a traditional Thai medicine, exhibits pharmacological activities such as anti-oxidant, anticancer, antibacterial, and anti-inflammatory properties. However, the low solubility of MGS is the major problem for the use in pharmaceutical industry. To enhance the solubility of this compound, the encapsulation of MGS by the three types of cyclodextrin including beta-cyclodextrin (BCD) 2,6-dimethyl-b-cyclodextrin (DMBCD) as well as 2-hydroxypropyl-b-cyclodextrin (HPBCD) was investigated. Based on molecular dynamic (MD) simulations, the results show the existence of several association complexes where the interaction of MGS on exterior CDs prior to a formation of inclusion complex. The van der Waals interaction (vdW) is the main contribution of the complex formation between MGS and CDs. The binding free energies are ranked as DMBCD < HPBCD < BCD. The MD simulations of free MGS with lipid bilayer show that the molecule rapidly inserts into the 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) surface, and then, penetrates deeply into the lipid tails (acyl groups) at 0.9 - 1.2 nm measured from the center of the lipid bilayer. DMBCD can translocate deeper into the hydrophobic region of the lipid bilayer, whilst BCD prefers to adsorb on the lipid surface, where the hydrogen bonds between secondary rim of those CDs and the lipid head groups (phosphate and glycerol ester) are the main contribution for the adsorption of CDs. The results from the release study of MGS from two CDs into the POPC membrane show that MGS dissociates from their hydrophobic pocket and subsequently penetrates into the interior of the lipid bilayer embedded beyond the phosphate groups of the POPC membrane, 0.9 - 1.2 nm apart from the center of lipid bilayer. Moreover, the free energy profile of the MGS release process was estimated using the potential of mean force (PMF). MGS has a local energy minimum of -9.0 kcal/mol at 0.8 nm from the center of lipid bilayer and consumes a energy barrier of 5.0 kcal/mol to locate at the center of the lipid bilayer. Thus, it prefers to locate in the hydrophobic rather than hydrophilic regions of the lipid bilayer. In contrast, the releasing of MGS from the hydrophobic pocket of DMBCD into lipid bilayer require a lower energy barrier of 2.1 kcal/mol. The above information leads us to conclude that the adsorption of MGS/DMBCD complexes on the lipid bilayer enhances the releasing of MGS into POPC membrane compared to free MGS through an increasing of hydrophobic interaction between DMBCD and the lipid acyl groups.