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Publication Abstract from PubMed

The cysteine biosynthetic pathway is absent in humans but essential in microbial pathogens, suggesting that it provides potential targets for the development of novel antibacterial compounds. CysK1 is a pyridoxalphosphate-dependent O-acetyl sulfhydrylase, which catalyzes the formation of L-cysteine from O-acetyl serine and hydrogen sulfide. Here we report nanomolar thiazolidine inhibitors of M. tuberculosis CysK1 developed by rational inhibitor design. The thiazolidine compounds were discovered using the crystal structure of a CysK1-peptide inhibitor complex as template. Pharmacophore modelling and subsequent in vitro screening gave an initial hit compound 2 (IC50 of 103.8 nM) which was subsequently optimized by a combination of protein crystallography, modelling, and synthetic chemistry. Hit expansion of 2 by chemical synthesis led to improved thiazolidine inhibitors with an IC50 value of 19 nM for the best compound, a 150 fold higher potency than the natural peptide inhibitor (IC50 2.9 microM).

Structure-Guided Design of Novel Thiazolidine Inhibitors of O-Acetyl Serine Sulfhydrylase from Mycobacterium tuberculosis.,Poyraz O, Jeankumar VU, Saxena S, Schnell R, Haraldsson M, Yogeeswari P, Sriram D, Schneider G J Med Chem. 2013 Jul 23. PMID:23879381^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.