The DOI matches its Crossref record; 22 of the 22 references it cites were found in a registry or an index.
Discovery of Potent Nonpeptide Inhibitors of Stromelysin Using SAR by NMR
Abstract
With the use of an NMR-based method, potent (IC 50 < 25 nM) nonpeptide inhibitors of the matrix metalloproteinase stromelysin (MMP-3) were discovered. The method, called SAR by NMR (for structure−activity relationships by nuclear magnetic resonance), involves the identification, optimization, and linking of compounds that bind to proximal sites on a protein. Using this technique, two ligands that bind weakly to stromelysin (acetohydroxamic acid, K D = 17 mM; 3-(cyanomethyl)-4‘-hydroxybiphenyl, K D = 0.02 mM) were identified. On the basis of NMR-derived structural information, the two fragments were connected to produce a 15 nM inhibitor of this enzyme. This compound was rapidly discovered (less than 6 months) and required only a minimal amount of chemical synthesis. These studies indicate that the SAR by NMR method can be effectively applied to enzymes to yield potent lead inhibitors an important part of the drug discovery process.
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Cites
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Twenty years on: the impact of fragments on drug discovery
Erlanson, D. A., Fesik, S. W., Hubbard, R. E., Jahnke, W., & Jhoti, H. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.109 · Cited by 1,000
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Metadata
- Authors
- Hajduk, P. J., Sheppard, G., Nettesheim, D. G., Olejniczak, E. T., Shuker, S. B., Meadows, R. P., Steinman, D. H., Carrera, G. M., Marcotte, P. A., Severin, J., Walter, K., Smith, H., Gubbins, E., Simmer, R., Holzman, T. F., Morgan, D. W., Davidsen, S. K., Summers, J. B., & Fesik, S. W.
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 1997-06-01
- Volume
- 119
- Issue
- 25
- Pages
- 5818-5827
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W2031609935
- Cited by
- 317
- References
- 22
- FWCI
- 6.15
- Type
- journal article
- Language
- en
- Open access
- closed
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- Hajduk, P. J., Sheppard, G., Nettesheim, D. G., Olejniczak, E. T., Shuker, S. B., Meadows, R. P., Steinman, D. H., Carrera, G. M., Marcotte, P. A., Severin, J., Walter, K., Smith, H., Gubbins, E., Simmer, R., Holzman, T. F., Morgan, D. W., Davidsen, S. K., Summers, J. B., & Fesik, S. W. (1997). Discovery of Potent Nonpeptide Inhibitors of Stromelysin Using SAR by NMR. Journal of the American Chemical Society. https://doi.org/10.1021/ja9702778
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