Parkinson’s disease is characterized by a decrease of dopamine levels within the brain. L-Dopa is commonly used in the clinical treatment of Parkinson ’s disease, as it is able to cross the blood brain barrier when dopamine cannot. DOPA-decraboxylase transforms L-DOPA into dopamine. Dopamine derived from L-DOPA is deactivated via metabolism by the COMT enzyme. Catechol-O-methyltransferase is an enzyme that degrades catecholamines such as dopamine, epinephrine, and norepinephrine. L-DOPA is a precursor of catecholamines and is therefore an important substrate of COMT. This targeted inhibition of the COMT enzyme prolongs the effectiveness of L-DOPA, resulting in a net increase in pharmacological efficiency. By selectively designing an inhibitor for the COMT enzyme, the effectiveness of L-DOPA can be extended through regulating the metabolism of dopamine derived from L-DOPA. The effectiveness of these dopaminergic derivatives has been measured via in silico models in which the strength of interaction between each substrate and the enzymatic active site was analyzed. A crystal-structure of the COMT enzyme active site, docked with a known COMT inhibitor, BIA 8-176, was isolated from the Protein Data Bank (PDB ID:2CL5). Novel dopaminergic derivatives were optimized using M062X/6-31G in vaccum and in implicit solvation with rigid amino acid side-chains. Interaction energies between ligands and the protein were then calculated using MO6L and the 6-311+G* basis set. A recently developed set of molecules that are more selective for increasing dopamine has been tested.

Design of novel inhibitors for the catechol-O-methyltransferase enzyme

2019 Spring National Meeting

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