Toward the Understanding of the Metabolism of Levodopa I. DFT Investigation of the Equilibrium Geometries, Acid-Base Properties and Levodopa-Water Complexes

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.

The Relationship Between COMT and MAO-B Gene Polymorphisms with Levodopa in Parkinson’s Disease Patients; A Review

“…Levodopa is a pro-drug to increase dopamine levels in Parkinson's disease patients (Elroby et al 2012). Following oral administration, Levodopa is absorbed in the duodenum and proximal jejunum, entering the bloodstream and gaining access to the brain by crossing the Blood-Brain Barrier (BBB) through a carrier-mediated process.…”

Conformation and electronic structure of Carbidopa. A QM/MD study

“…This starts with identifying and localizing the geometry of the global minimum energy structure of CD. In a previous communication, we have investigated the electronic structure and mechanism of decarboxylation of LD 11,12 and its water complexes. In the present communication, we present a thorough investigation of the electronic structure and bonding characteristics of CD.…”