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. 2012;13(4):4321-4339.
doi: 10.3390/ijms13044321. Epub 2012 Apr 2.

Toward the understanding of the metabolism of levodopa I. DFT investigation of the equilibrium geometries, acid-base properties and levodopa-water complexes

Shabaan A K Elroby  1   2 , Mohamed S I Makki  1 , Tariq R Sobahi  1 , Rifaat H Hilal  1   3
Affiliations

Toward the understanding of the metabolism of levodopa I. DFT investigation of the equilibrium geometries, acid-base properties and levodopa-water complexes

Shabaan A K Elroby et al. Int J Mol Sci. 2012.

Abstract

Levodopa (LD) is used to increase dopamine level for treating Parkinson's disease. The major metabolism of LD to produce dopamine is decarboxylation. In order to understand the metabolism of LD; the electronic structure of levodopa was investigated at the Density Functional DFT/B3LYP level of theory using the 6-311+G** basis set, in the gas phase and in solution. LD is not planar, with the amino acid side chain acting as a free rotator around several single bonds. The potential energy surface is broad and flat. Full geometry optimization enabled locating and identifying the global minimum on this Potential energy surface (PES). All possible protonation/deprotonation forms of LD were examined and analyzed. Protonation/deprotonation is local in nature, i.e., is not transmitted through the molecular framework. The isogyric protonation/deprotonation reactions seem to involve two subsequent steps: First, deprotonation, then rearrangement to form H-bonded structures, which is the origin of the extra stability of the deprotonated forms. Natural bond orbital (NBO) analysis of LD and its deprotonated forms reveals detailed information of bonding characteristics and interactions across the molecular framework. The effect of deprotonation on the donor-acceptor interaction across the molecular framework and within the two subsystems has also been examined. Attempts to mimic the complex formation of LD with water have been performed.

Keywords: DFT; NBO; levodopa; parkinson’s disease; protonation/deprotonation.

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Figures

Figure 1
Figure 1
Numbering system of LD adopted in the present work and optimized geometric parameters computed at different levels of theory.
Figure 1
Figure 1
Numbering system of LD adopted in the present work and optimized geometric parameters computed at different levels of theory.
Figure 1
Figure 1
Numbering system of LD adopted in the present work and optimized geometric parameters computed at different levels of theory.
Figure 2
Figure 2
Geometrical parameters (bond lengths (Ǻ) and natural bond orbital (NBO) charge distribution) for deprotonated structures of levodopa.
Figure 2
Figure 2
Geometrical parameters (bond lengths (Ǻ) and natural bond orbital (NBO) charge distribution) for deprotonated structures of levodopa.
Figure 2
Figure 2
Geometrical parameters (bond lengths (Ǻ) and natural bond orbital (NBO) charge distribution) for deprotonated structures of levodopa.
Figure 3
Figure 3
Geometrical parameters (bond lengths (Ǻ)) of the protonated forms for LD computed at the B3LYP/6-311+G** level.
Figure 3
Figure 3
Geometrical parameters (bond lengths (Ǻ)) of the protonated forms for LD computed at the B3LYP/6-311+G** level.
Figure 4
Figure 4
Optimized structures for the LD-water (distances in Ǻ).
Chart 1
Chart 1
Two pathways of Levodopa (LD) metabolism.
See this image and copyright information in PMC

References

    1. Dauer W., Przedborski S. Parkinson’s disease: Mechanism and models. Neuron. 2003;39:889–909. - PubMed
    1. Nutt J.G., Fellman J.H. Pharmacokinetics of levodopa. Clin. Neuropharmacol. 1984;7:35–49. - PubMed
    1. Goodal M.C., Alton H. Metabolism of 3,4-dihydroxyphenylalanine (l-dopa) in human subjects. Biochem. Pharmacol. 1972;21:2401–2408. - PubMed
    1. Montgomery E.B. Pharmacokinetics and pharmacodynamics of levodopa. Neurology. 1992;42:17–22. - PubMed
    1. Tyce G.M. Metabolism of 3,4-dihydroxyphenylalanine by isolated perfused rat liver. Biochem. Pharmacol. 1971;20:3447–3462. - PubMed

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