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Profiling the NIH Small Molecule Repository for compounds that generate H2O2 by redox cycling in reducing environments. | LitMetric

Profiling the NIH Small Molecule Repository for compounds that generate H2O2 by redox cycling in reducing environments.

Assay Drug Dev Technol

Pittsburgh Molecular Library Screening Center, Drug Discovery Institute, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.

Published: April 2010

AI Article Synopsis

  • The study screened two libraries—LOPAC and NIH SMR—to discover compounds that generate hydrogen peroxide (H2O2) when exposed to specific conditions, identifying two key compounds in the LOPAC library and 37 potential candidates in the NIH SMR library.
  • A variety of chemical structures were found to exhibit redox cycling activity (RCC), with high confirmation rates for ortho-quinones and pyrimidotriazinediones, whereas only a small percentage of para-quinones were confirmed as RCCs.
  • The identified RCCs showed diverse bioactivity, interacting with multiple protein targets and inhibiting cell growth, which suggests that screening for RCCs in compound libraries can streamline the drug discovery process by quickly identifying

Article 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3098569PMC
http://dx.doi.org/10.1089/adt.2009.0247DOI Listing

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