The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
PAINS in the Assay: Chemical Mechanisms of Assay Interference and Promiscuous Enzymatic Inhibition Observed during a Sulfhydryl-Scavenging HTS
Open accessAbstract
Significant resources in early drug discovery are spent unknowingly pursuing artifacts and promiscuous bioactive compounds, while understanding the chemical basis for these adverse behaviors often goes unexplored in pursuit of lead compounds. Nearly all the hits from our recent sulfhydryl-scavenging high-throughput screen (HTS) targeting the histone acetyltransferase Rtt109 were such compounds. Herein, we characterize the chemical basis for assay interference and promiscuous enzymatic inhibition for several prominent chemotypes identified by this HTS, including some pan-assay interference compounds (PAINS). Protein mass spectrometry and ALARM NMR confirmed these compounds react covalently with cysteines on multiple proteins. Unfortunately, compounds containing these chemotypes have been published as screening actives in reputable journals and even touted as chemical probes or preclinical candidates. Our detailed characterization and identification of such thiol-reactive chemotypes should accelerate triage of nuisance compounds, guide screening library design, and prevent follow-up on undesirable chemical matter.
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Modulation of histone H3 lysine 56 acetylation as an antifungal therapeutic strategy
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Nelson, K. M., Dahlin, J. L., Bisson, J., Graham, J., Pauli, G. F., & Walters, M. A. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00975 · Cited by 1,956
Self-citationA Perspective on the Kinetics of Covalent and Irreversible Inhibition
Strelow, J. M. (2017) · SLAS Discovery · doi:10.1177/1087057116671509 · Cited by 392
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Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease
Zhang, Z., Obianyo, O., Dall, E., Du, Y., Fu, H., Liu, X., Kang, S. S., Song, M., Yu, S.-P., Cabrele, C., et al. (2017) · Nature Communications · doi:10.1038/ncomms14740 · Cited by 146
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Metadata
- Authors
- Dahlin, J. L., Nissink, J. W. M., Strasser, J. M., Francis, S., Higgins, L., Zhou, H., Zhang, Z., & Walters, M. A.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2015-02-21
- Volume
- 58
- Issue
- 5
- Pages
- 2091-2113
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2332896222
- Cited by
- 351
- References
- 6
- FWCI
- 38.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Dahlin, J. L., Nissink, J. W. M., Strasser, J. M., Francis, S., Higgins, L., Zhou, H., Zhang, Z., & Walters, M. A. (2015). PAINS in the Assay: Chemical Mechanisms of Assay Interference and Promiscuous Enzymatic Inhibition Observed during a Sulfhydryl-Scavenging HTS. Journal of Medicinal Chemistry. https://doi.org/10.1021/jm5019093
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