L-DOPA is commonly used as a xenobiotic for patients with conditions such as Parkinson’s disease. Clinically administered L-DOPA is transformed into dopamine by DOPA-decarboxylase. In order to be pharmacologically effective, L-DOPA must not be metabolized before it crosses the blood brain barrier. In order to prevent premature metabolism, DOPA-decarboxylase may be inhibited in the periphery. By selectively designing an inhibitor for the DOPA-decarboxylase enzyme, the effectiveness of the L-DOPA can be extended. A suite of dopaminergic derivatives have been developed as potential inhibitors of the DOPA-decarboxylase enzyme. The inhibitory 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 DOPA-decarboxylase active site, docked with a known DOPA-decarboxylase inhibitor, Carbidopa, was isolated from the Protein Data Bank (PDB ID: 1JS3). The positions of novel dopaminergic derivatives were optimized in the active site using M062X/6-31G with implicit solvation and with flexible amino acid side-chains. Interaction energies between the ligands and the protein were calculated using M062X and MP2 with the 6- 311+G* basis set. At present, 6-cyanodopamine appears to be an effective competitive inhibitor of the DOPA-decarboxylase enzyme.

DFT study of the selectivity of DOPA-decarboxylase

251st National Meeting (2016)

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