Application of computer modeling to the study of nimesulide inclusion complexes with β- and γ-cyclodextrin

The incapsulation of low-soluble pharmaceutical agents in the β- and γ-cyclodextrin cavity (β-CD, γ-CD) successfully solves the current issues related to bioavailability and dose reduction of a variety of anti-inflammatory drugs. This study is focused on nimesulide (Nim), a nonsteroidal anti-inflammatory drug (NSAID).

The molecular complexation of nim/β-CD and nim/ γ-CD was modelled via the Gaussian 09W computer program using the B3LYP method for DFT calculation. Molecular dynamics simulations of the complexes were performed via the NAMD2 software.

The set of conformations, characterized by lowest potential energy was obtained by Gaussian 09W for the nim/β-CD and nim/ γ-CD molecular systems. The results of calculations indicated a low probability of complexation under the standard conditions. Nimesulide molecule exhibits a steric hindrance, leading to instability of the nim/β-CD complex with minimal bond distances of 1.92Å. At the same time, nim/ γ-CD complex shares a higher stability due to the larger dimensions of the carrier molecule. Conformational analysis indicated a deep minima in the product area of the plot, demonstrating stability of the nim/ γ-CD system.

The stability of the nim/ β -CD complex was studied using molecular dynamics approaches. The simulation with length of 5 ns was performed via the NAMD2 computer program using the CHARMM36 forcefield. The further analysis including visualization and data plotting was comleted by the VMD software (V1.9.4). The idea of hydrophobic–hydrophilic interactions between molecules was confirmed by the obtained data. In addition, lack of dissociation of nim/β-CD complex was observed during the entire period of simulation. Stability of complex was also proved by RMSD trajectories analysis, as the corresponding curves were not drastically deviated.

Obtained data support the idea of complexation and relative stability of complexes. The approaches of computational chemistry in study of supramolecules provide deep insights into complexation and make it possible to evaluate affinity.