Complexos de inclusão de levodopa em β-ciclodextrina: uma análise computacional da degradação da levodopa

Abstract

Levodopa is a dopaminergic precursor that undergoes a decarboxylation reaction; this process occurs spontaneously and at a high rate, which may compromise its efficiency as a pharmaceutical agent. In this context, β-cyclodextrin (β-CD) has been investigated for the formation of inclusion complexes capable of modifying the physicochemical properties of guest molecules. In this work, the decarboxylation reaction of levodopa was studied using Density Functional Theory (DFT), molecular dynamics simulations (employed to evaluate structural stability over time), and non-covalent interaction (NCI) analysis (used to identify weak interactions such as van der Waals forces and hydrogen bonding), considering the inclusion of levodopa within β-CD. Geometries were optimized at the M06-2X/6-31G(d,p) level, with transition states characterized by a single imaginary frequency: ν = 1799.44i cm⁻¹ for levodopa in the gas phase and ν = 1646.84i cm⁻¹ under implicit solvation. For systems involving β-CD, complex A’ exhibited an imaginary frequency of ν = 1686.54i cm⁻¹. Intrinsic reaction coordinate (IRC) analysis confirmed the connection between reactants and products in both gas phase and implicit solvation (IEFPCM). The Gibbs free energy of activation (ΔG‡) was 67.732 kcal·mol⁻¹ in the gas phase and 70.560 kcal·mol⁻¹ under implicit solvation for levodopa, while for β-CD systems the values remained of the same order of magnitude, preventing a conclusive inference regarding changes in the energy barrier. Four structures (A’, B’, C’, and D’) were identified, with D’ being the most stable, presenting ΔG = 8.788 kcal·mol⁻¹ under implicit solvation and ΔG = −13.160 kcal·mol⁻¹ in the gas phase, followed by B’ and A’. Structure C’ exhibited ΔG > 0, with stability mainly associated with enthalpic contribution (ΔH), which predominates in the composition of ΔG in the gas phase. NCI analysis indicated a predominance of van der Waals interactions (RDG ≈ 0.2–0.5), while QTAIM analysis confirmed the presence of hydrogen bonds (ρ ≈ 0.002–0.035 a.u.). Molecular dynamics simulations showed that complexes B’ and D’ are structurally stable, with average RMSD values of ~0.14 nm (B’) and ~0.12 nm (D’), indicating lower structural fluctuation and greater relative stability for D’. Overall, the results suggest that the formation of the inclusion complex with β-CD promotes structural and energetic changes in levodopa; however, it was not possible to conclusively establish modulation of the decarboxylation process.