ArticleAssay and drug development technologies2010
Profiling the NIH Small Molecule Repository for compounds that generate H2O2 by redox cycling in reducing environments.
Article in Assay and drug development technologies, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed.
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- Exponential amplification by redox cross-catalysis and unmasking of doubly protected molecular probes.Chemical science · 2022Article
- Gains from no real PAINS: Where 'Fair Trial Strategy' stands in the development of multi-target ligands.Acta pharmaceutica Sinica. B · 2021Review
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- Next-Generation Cell-Active Inhibitors of the Undrugged Oncogenic PTP4A3 Phosphatase.The Journal of pharmacology and experimental therapeutics · 2019Article
- The diverse mechanisms and anticancer potential of naphthoquinones.Cancer cell international · 2019Review
- High-throughput screening with nucleosome substrate identifies small-molecule inhibitors of the human histone lysine methyltransferase NSD2.The Journal of biological chemistry · 2018Article
- Investigating the Behavior of Published PAINS Alerts Using a Pharmaceutical Company Data Set.ACS medicinal chemistry letters · 2018Article
- Small Molecules Identified from a Quantitative Drug Combinational Screen Resensitize Cisplatin's Response in Drug-Resistant Ovarian Cancer Cells.Translational oncology · 2018Article
- ALARM NMR for HTS triage and chemical probe validation.Current protocols in chemical biology · 2018Article
- Assay interference and off-target liabilities of reported histone acetyltransferase inhibitors.Nature communications · 2017Article
- Mimicking Intermolecular Interactions of Tight Protein-Protein Complexes for Small-Molecule Antagonists.ChemMedChem · 2017Article
- A Computational Investigation of Small-Molecule Engagement of Hot Spots at Protein-Protein Interaction Interfaces.Journal of chemical information and modeling · 2017Article
- Understanding and predicting the potency of ROS-based enzyme inhibitors, exemplified by naphthoquinones and ubiquitin specific protease-2.Chemical science · 2016Article
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8 authors.
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Abstract
We have screened the Library of Pharmacologically Active Compounds (LOPAC) and the National Institutes of Health (NIH) Small Molecule Repository (SMR) libraries in a horseradish peroxidase-phenol red (HRP-PR) H2O2 detection assay to identify redox cycling compounds (RCCs) capable of generating H2O2 in buffers containing dithiothreitol (DTT). Two RCCs were identified in the LOPAC set, the ortho-naphthoquinone beta-lapachone and the para-naphthoquinone NSC 95397. Thirty-seven (0.02%) concentration-dependent RCCs were identified from 195,826 compounds in the NIH SMR library; 3 singleton structures, 9 ortho-quinones, 2 para-quinones, 4 pyrimidotriazinediones, 15 arylsulfonamides, 2 nitrothiophene-2-carboxylates, and 2 tolyl hydrazides. Sixty percent of the ortho-quinones and 80% of the pyrimidotriazinediones in the library were confirmed as RCCs. In contrast, only 3.9% of the para-quinones were confirmed as RCCs. Fifteen of the 251 arylsulfonamides in the library were confirmed as RCCs, and since we screened 17,868 compounds with a sulfonamide functional group we conclude that the redox cycling activity of the arylsulfonamide RCCs is due to peripheral reactive enone, aromatic, or heterocyclic functions. Cross-target queries of the University of Pittsburgh Drug Discovery Institute (UPDDI) and PubChem databases revealed that the RCCs exhibited promiscuous bioactivity profiles and have populated both screening databases with significantly higher numbers of active flags than non-RCCs. RCCs were promiscuously active against protein targets known to be susceptible to oxidation, but were also active in cell growth inhibition assays, and against other targets thought to be insensitive to oxidation. Profiling compound libraries or the hits from screening campaigns in the HRP-PR H(2)O(2) detection assay significantly reduce the timelines and resources required to identify and eliminate promiscuous nuisance RCCs from the candidates for lead optimization.
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