Profiling the NIH Small Molecule Repository for Compounds That Generate H₂O₂by Redox Cycling in Reducing Environments

Abstract

We have screened the Library of Pharmacologically Active Compounds (LOPAC) and the National Institutes of Health (NIH)Small

Aminothienopyridazines and Methylene Blue Affect Tau Fibrillization via Cysteine Oxidation

“…This raised the possibility that the active ATPZs facilitated cysteine oxidation through a catalytic redox cycling mechanism that might involve the generation of reactive superoxide or hydrogen peroxide. Such redox cycling between heterocyclic compounds and thiols has been previously noted (40). To determine whether this was the case, the level of peroxide was compared after CNDR-51348 was incubated in the absence or presence of K18PL for 6 h at a concentration (20 M) typically used in Tau fibrillization reactions.…”

“…revealed that many false positives are obtained with compounds that are capable of redox cycling in the presence of a reducing agent (33,40). Among the secondary analyses conducted on the APTZs identified from this screen was a caspase-8 enzyme assay that is sensitive to oxidizing agents (26,47).…”

A Time-Resolved Fluorescence Resonance Energy Transfer Assay for High-Throughput Screening of 14-3-3 Protein–Protein Interaction Inhibitors

“…Remarkably, two compounds showed activity only in our 14-3-3 inhibitor screening among more than 600 bioassays profiled ( Table 2). For comparison, we also analyzed the data for 37 well-defined promiscuous compounds, which are known redox cycling compounds (RCCs) that are capable of generating H 2 O 2 in buffers containing dithiothreitol 39 and summarized the data with updated information from the PubChem database (Table 3). For these 37 compounds, the average number of total bioassays tested for each compound is 563.…”

Identification and Characterization of Novel Inhibitors of Mammalian Aspartyl Aminopeptidase

“…However, compounds that are strongly fluorescent, colored, poorly soluble, or redox-active could give false-positive readings due to their ability to interfere with the fluorescence emission readout of the assay. These compounds needed to be distinguished from true hits before further investigation (Simeonov et al, 2008;Baell and Holloway, 2010;Soares et al, 2010). To identify true modulators of DNPEP activity, we employed a LC-MS-based method that directly measures products of DNPEP-catalyzed hydrolysis of the physiologic peptide substrate, Ang II (Chen et al, 2012) (Figs.…”