Design of Novel Inhibitors for the Aldehyde Dehydrogenases

Abstract

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. Ligands can fit into the active site in a number of ways; this work examines single molecules orientations and double molecule orientations. 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 such as the MP and CM series. Mutant enzymes were also studied for their affinity for the ligands.