title: Structure-guided design of novel thiazolidine inhibitors of O-acetyl serine sulfhydrylase from Mycobacterium tuberculosis.
abstract: 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 Mycobacterium 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 modeling and subsequent in vitro screening resulted in an initial hit compound 2 (IC50 of 103.8 nM), which was subsequently optimized by a combination of protein crystallography, modeling, 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 μM).
authors.affiliation: Division of Molecular Structural Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Omer
authors.initials: O
authors.lastname: Poyraz
authors.forename: Variam Ullas
authors.initials: VU
authors.lastname: Jeankumar
authors.forename: Shalini
authors.initials: S
authors.lastname: Saxena
authors.forename: Robert
authors.initials: R
authors.lastname: Schnell
authors.forename: Martin
authors.initials: M
authors.lastname: Haraldsson
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
authors.forename: Gunter
authors.initials: G
authors.lastname: Schneider
mesh_terms: D003547:Cysteine Synthase / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D004791:Enzyme Inhibitors; D003547:Cysteine Synthase