L-DOPA is commonly used as a xenobiotic for patients with conditions such as Parkinson’s disease. L-DOPA is transformed into dopamine by DOPA-decarboxylase. Dopamine derived from L-DOPA is deactivated via metabolism by a series of enzymes including Aldehyde dehydrogenases (ALDH). The targeted inhibition of the ALDH enzyme may help to prolong the effectiveness of L-DOPA, resulting in a net increase in pharmacological efficiency. By selectively designing an inhibitor for ALDH, the effectiveness of the L-DOPA can be extended by regulating the metabolism of dopamine derived from L-DOPA. The effectiveness of a series of potential inhibitors 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 ALDH enzyme with an inhibitor bound in its active site (PDB ID: 4WP7) was used to create a model of the active site. Novel dopaminergic derivatives were optimized in the active site using M062X/6-31G with implicit solvation and with relaxed amino acid side-chains. Models with two ligands in the active site were explored along with point mutations to more fully understand binding of the ligands. Interaction energies between the ligands and the protein were calculated using MO62X with the 6-311+G* basis set. Some potential inhibitors show promising results.

Design of novel inhibitors for the aldehyde dehydrogenases

253rd National Meeting (2017)

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