Discovery of Potent Nonpeptide Inhibitors of Stromelysin Using SAR by NMR

Autor:	E. Gubbins, D. W. Morgan, Edward T. Olejniczak, Jean M. Severin, S. K. Davidsen, G. Sheppard, G. M. Carrera, Robert L. Simmer, D. H. Steinman, David G. Nettesheim, R. P. Meadows, T. F. Holzman, and J. B. Summers, H. Smith, P. A. Marcotte, Suzanne B. Shuker, Philip J. Hajduk, Karl A. Walter, Stephen W. Fesik
Rok vydání:	1997
Předmět:	chemistry.chemical_classification Drug discovery Stereochemistry Acetohydroxamic acid A protein General Chemistry Matrix metalloproteinase Biochemistry Combinatorial chemistry Chemical synthesis Catalysis Colloid and Surface Chemistry Enzyme chemistry Yield (chemistry) medicine IC50 medicine.drug
Zdroj:	Journal of the American Chemical Society. 119:5818-5827
ISSN:	1520-5126 0002-7863
DOI:	10.1021/ja9702778
Popis:	With the use of an NMR-based method, potent (IC50 < 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, KD = 17 mM; 3-(cyanomethyl)-4‘-hydroxybiphenyl, KD = 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 inhibitorsan important part of the drug discovery process.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::08e458e8b044870f08d7fbd35c1a163e https://doi.org/10.1021/ja9702778 Zobrazit plný text záznamu