Analogs of Carbidopa: in Silico Design & Development of Novel Dopa Decarboxylase Inhibitors in the Treatment of Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Pharmacotherapy with levodopa in combination with carbidopa provides symptomatic relief in patients suffering from PD. However, several studies have been conducted in an attempt to improve the therapeutic efficiency of levodopa by using drugs that preferentially inhibit extracerebral decarboxylase. Yet, none of them has shown convincingly significant results. In this study, we have used computational methods to design novel carbidopa analogues and evaluated them for interaction with the enzyme DOPA decarboxylase (DDC) through in silico analysis. Here, we report that carbidopa analogue-8 ((S)-3-(3,4-dihydroxyphenyl)-2-(hydroxyamino)-2-methylpropanoic acid) has shown higher affinity and better interaction with DDC than carbidopa. DDC protein interactions with carbidopa analogues were confirmed by binding energy given by GOLD docking software. KeywordsParkinson’s disease, carbidopa, levodopa and DOPA decarboxylase. INTRODUCTION Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by resting tremor, rigidity, bradykinesia and gait impairment. It is estimated that approximately 1-2% of the population over the age of 60 years are affected [1]. Pathological hallmarks for PD include degeneration of dopaminergic neurons in the substantia nigra with consequent depletion of the neurotransmitter dopamine. Dopamine depletion causes major physiological disruptions in the basal ganglia-thalamocortical motor circuit, which is responsible for controlling the motor activity [2]. At present, there is no cure for PD. However, dopamine replacement therapy with levodopa, a dopamine precursor resulted in significant symptomatic relief [3]. Levodopa is converted to dopamine by an enzyme known as DOPA decarboxylase (DDC). But the chronic use of levodopa is associated with development of motor fluctuations and dyskinesia [4]. When oral dose of levodopa is administered, about 95% of the drug is metabolized in extracerebral tissues causing a dramatic reduction in the amount of levodopa available for transport to the brain. Moreover, peripheral decarboxylation of levodopa to dopamine causes prominent nausea and vomiting [5]. To overcome these side effects, levodopa is administered with a DDC inhibitor such as carbidopa. These DDC inhibitors do not penetrate through blood-brain barrier and show their inhibitory action mainly at extracerebral tissues. Even though the combinational treatment with levodopa and carbidopa provide symptomatic relief, the pharmacological therapy can be more effective if DDC inhibitors that possess higher affinity than carbidopa are administered. In this computational study, we report few analogues of carbidopa that show higher affinity and better interaction with the enzyme DDC. These results have been confirmed by the binding energy given by GOLD docking software. MATERIALS AND METHODS: Ligand and protein preparationThe enzyme DOPA decarboxylase was retrieved from the RCSB Protein Data Bank (http://www.rcsb.org/pdb/) with PDB Id1JS3 [6]. Active sites of the enzyme were identified by RCSB PDB Ligand Explorer and M Lakshmi Vasavi Devi et al /J. Pharm. Sci. & Res. Vol.3(4), 2011,1176-1181