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Browsing by Author "Nastase, Anthony F."
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Item Data Mining and Quantitative Structure-Activity Relationships of Inhibitors for Treating Alzheimer's Disease(Office of the Vice Chancellor for Research, 2012-04-13) Nastase, Anthony F.; Boyd, Donald B.Amyloid cleaving enzyme-1 (BACE1) is a target of interest for treating patients with Alzheimer’s disease (AD). As of 2007, more than 37 million people worldwide are afflicted with the disease. Incidence of the disease keeps increasing as the population ages and fewer people die of other diseases. ß-Amyloid precursor protein (APP) is a natural protein associated with neurons of the brain. In Alzheimer's disease, APP is cleaved by BACE1 at the beta-site, resulting in short 42 amino acid segments called amyloid-ß (Aß). Aggregation of Aß into plaques results in the death of neurons and is associated with AD. Inhibition of the BACE1 enzyme may prevent Aß formation and prevent the development or progression of AD. Known BACE1 inhibitors are analyzed using computational chemistry techniques, and quantitative structure-activity relationships (QSAR) are developed.Item Simple Structure-Based Approach for Predicting the Activity of Inhibitors of Beta-Secretase (BACE1) Associated with Alzheimer's Disease(Office of the Vice Chancellor for Research, 2013-04-05) Nastase, Anthony F.; Boyd, Donald B.Beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) is a target of interest for treating patients with Alzheimer’s disease (AD). Inhibition of BACE1 may prevent amyloid-ß (Aß) plaque formation and the development or progression of Alzheimer’s disease. Known BACE1 inhibitors were analyzed using computational chemistry and cheminformatics techniques to search for quantitative structure− activity relationships (QSAR). A remarkable relationship was found with only two simple descriptors with a square of the linear correlation coefficient r2 of 0.75. The main descriptor is the number of hydrophobic contacts in the range 4−5 Å between the atoms of the ligand and active site. The other descriptor is the number of short (<2.8 Å) hydrogen bonds. Our approach uses readily available structural data on protein- inhibitor complexes in the Protein Data Bank (PDB) but would be equally applicable to proprietary structural biology data. The findings can aid structure-based design of improved BACE-1 inhibitors. If an inhibitor has less observed activity than predicted by our correlation, the compound should be retested because the first assay may have underestimated the compound’s true activity.