Molecular modeling study of Lamotrigine/β-cyclodextrin inclusion complex

We investigated the inclusion process of Lamotrigine (LMN) in beta cyclodextrin (β-CD) with 1:1 stoichiometry using empirical, semi-empirical and quantum mechanical calculations models. We have found that the quantum and hybrid ONIOM2 methods gave the most favorable orientation in which the guest molecule is totally sequestered in the hydrophobic cavity of the cyclodextrin with the tiazine ring located near the primary hydroxyls of the β-CD and the dichloro phenyl moiety near the secondary hydroxyls with no hydrogen bonding formation. Moreover, the statistical thermodynamic calculations at 1 atm and 298.15 K demonstrate that 1:1 LMN/β-CD complexation is an exothermic process, enthalpically favorable in nature and that non bonded Van der Waals interactions represent the mainly driving forces leading to complex stability. While, HOMO and LUMO orbital investigations confirm on one hand the better stability of 'A' orientation and on the other hand prove that no significant change will be observed in the electronic structure of LMN after complexation.