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Design of Novel Inhibitors for the Aldehyde Dehydrogenases
Magee, Caroline A. Selner, Emma F. Peterson, Larryn W.
Magee, Caroline A.
Selner, Emma F.
Peterson, Larryn W.
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URCAS, Student research, 2018 Spring, Class of 2018, Class of 2019, Chemistry, Department of, Aldehyde dehydrogenase, Parkinson's disease, Inhibitors, Dopamine receptor, L-Dopa
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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.
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Presentation by Caroline Magee ('19), Emma Selner ('18), and Larryn Peterson delivered at the Rhodes College Undergraduate Research and Creative Activity Symposium (URCAS).