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Inclusion of Levodopa into β-Cyclodextrin: A Comprehensive Computational Study.

ABSTRACT: This study focused on the inclusion of levodopa (LVDP) into β-cyclodextrin (BCD) using various computational methods such as quantum mechanics (QM), molecular dynamics/steered molecular dynamics (MD/SMD), and QM/molecular mechanics/Poison-Boltzmann surface area (QM/MM/PBSA). The QM results assigned the most significant charge-transfer atoms and the higher stability of LVDP in the aqueous phase. The MD results indicate the formation of a 1:1 complex with a reasonable estimation of the effective radius of the complex, the significant contribution of hydrogen bonding in the binding energy, and the enhancement of the water solubility of LVDP. By accounting for the water hydrogen bonds and their dipolar effects, QM/MM calculations lead to the more accurate IR spectrum and binding energy of the BCD-LVDP complex. By considering carboxylic and amine functional groups' more precise arrangement, QM/MM assigns stronger hydrogen bonds between LVDP and BCD. While all the methods provide a reasonable estimation of the binding energy, the most accurate value (-4.14 kcal/mol) is obtained from QM/MM/PBSA.

SUBMITTER: Rezaeisadat M

PROVIDER: S-EPMC8459354 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Inclusion of Levodopa into β-Cyclodextrin: A Comprehensive Computational Study.

Rezaeisadat Morteza M Salehi Nafiseh N Bordbar Abdol-Khalegh AK

ACS omega 20210907 37

This study focused on the inclusion of levodopa (LVDP) into β-cyclodextrin (BCD) using various computational methods such as quantum mechanics (QM), molecular dynamics/steered molecular dynamics (MD/SMD), and QM/molecular mechanics/Poison-Boltzmann surface area (QM/MM/PBSA). The QM results assigned the most significant charge-transfer atoms and the higher stability of LVDP in the aqueous phase. The MD results indicate the formation of a 1:1 complex with a reasonable estimation of the effective r ...[more]

PMID: 34568661

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Project description:BackgroundFlunarizine dihydrochloride (FLN) is used in the prophylactic treatment of migraine, vertigo, occlusive peripheral vascular disease and epilepsy. Cyclodextrins (CDs) are chiral, truncated cone shaped macrocycles known for their inner hydrophobic and outer hydrophilic site. They form complexes with hydrophobic drug molecules and enhance the solubility and bioavailability of such compounds by enhancing drug permeability through mucosal tissues. NMR spectroscopy and computational docking have been recognized as an important tool for the interaction study of CDs-drug inclusion complexes in solution state.ResultsThe structural assignments of FLN and β-CD protons were determined by 1H NMR and 2D 1H-1H COSY NMR spectroscopy. 1H NMR spectroscopic studies of FLN, β-CD and their mixtures confirmed the formation of β-CD-FLN inclusion complex in solution. 1H NMR titration data for β-CD-FLN inclusion complex showed 1:1 stoichiometry, an association constant of K a = 157 M-1 and change in Gibbs free energy of ∆G = - 12.65 kJ mol-1. The binding constant of the β-CD inclusion complex with two nearly similar structures, FLN and cetirizine dihydrochloride, were compared. Two-dimensional 1H-1H ROESY spectral data and molecular docking studies showed the modes of penetration of the aromatic rings from the wider rim side into the β-CD cavity. The possible geometrical structures of the β-CD-FLN inclusion complex have been proposed in which aromatic rings protrude close to the narrower rim of the β-CD truncated cone.ConclusionNMR spectroscopic studies of FLN, β-CD and FLN:β-CD mixtures confirmed the formation of 1:1 inclusion complex in solution at room temperature. Two-dimensional 1H-1H ROESY together with molecular docking study confirmed that the F-substituted aromatic ring of FLN penetrates into β-CD truncated cone and the tail of aromatic rings were proximal to narrower rim of β-CD. The splitting of aromatic signals of FLN in the presence of β-CD suggests chiral differentiation of the guest FLN by β-CD.

Dataset Information

Inclusion of Levodopa into β-Cyclodextrin: A Comprehensive Computational Study.

Publications

Inclusion of Levodopa into β-Cyclodextrin: A Comprehensive Computational Study.

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