Discovery of a Novel Arginase I Inhibitors by a Validated Virtual Screening and Docking Work-Flow
Date of Award
Master of Science (MS)
Joseph Audie, Ph.D.
The primary purpose of this study was to use a virtual screening pipeline to identify novel inhibitors for Human arginase 1 by using in silico chemical library screening and molecular docking using the Vina docking program. Importantly, the molecular docking procedure employed was rigorously validated by (1) accurately reproducing IC₅₀ and binding constant (Ki) trends for two disparate families of arginase inhibitors and by (2) accurately re-constructing four arginise-ligand complexes through re-docking. The first family of arginase inhibitors included ten flavonoid compounds; the second family of inhibitors included five aminoimidazole analogues. Three of the four arginase complexes used in the re-docking study were of human origin and included the ligands L-omithine, L-lysine and N-OMEGA-HYDROXY-LARGININE. The fourth arginase enzyme used in the re-docking study was derived from Schistosoma mansoni and involved re-docking L-Valine. Taken collectively, the results of the validation studies strongly indicate the usefulness of Vina for predicting novel arginase inhibitors. To build a virtual chemical library for docking analysis, the ZINC chemical database was filtered for flavonoid-like compounds. The compounds were ultimately docked into the arginase active site and evaluated for their ADMET properties, resulting in the identification of compounds were ultimately docked into the ZINC8442161 as the most promising arginase inhibitor. Future research will focus on in vitro testing of selected arginase inhibitors predicted in this study.
Baribault, Brianna, "Discovery of a Novel Arginase I Inhibitors by a Validated Virtual Screening and Docking Work-Flow" (2016). Chemistry Master’s Theses. 58.