Computational Screening and Validation of Suitable Natural Compounds Against Peripheral Metabolism of L-Dopa: An Alternative Approach Towards Treatment of Parkinson’s Disease
Posted: 19 Feb 2020
Date Written: February 19, 2020
Abstract
Progressive loss of dopaminergic neurons within substantia nigra pars compacta causes motor related symptoms in Parkinson’s disease (PD). Therefore, administration of exogenous Levodopa (L-DOPA) has become a common practise to maintain the dopamine level within the midbrain which provides symptomatic relief to PD patients. But, peripheral degradation of (L-DOPA) occurs due to enzymatic activity of two major proteins such as Dopa decarboxylase (DDC, E.C. 4.1.1.28) and Catechol-O-methyltransferase (COMT, EC 2.1.1.6) therefore only 1-5% of L-DOPA reaches to dopaminergic neurons. To get rid of this situation, few peripheral DDC inhibitors (Carbidopa or Benserazide) and COMT inhibitors (Entacapone or Tolcapone) are co-supplemented along with L-DOPA therapy to prolong the availability of L-DOPA within the brain. On the contrary, as PD is an irreversible disorder thus continuous use of those synthetic drugs induces threat to patient’s hepatic and cardiac health which has risen as a major problem. Therefore, scientific community have been focused to discover suitable drug like natural compounds as an alternative of synthetic medicines. In this context, the present study is planned for in silico discovery of bioactive compounds and evaluation of their effectiveness as potent inhibitors against human DDC and COMT through virtual screening, molecular docking, ADMET analysis, pharmacophore study, and molecular dynamics simulation. This study identified few potent plant oriented drug like natural compounds with good inhibitory effect against both peripheral COMT and DDC and thus may be extended for further experimental validation to be used as adjuvant therapy in L-DOPA treatment.
Keywords: Parkinson’s disease, levodopa, DDC, COMT, natural compounds
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