title: Discovery of novel nitrobenzothiazole inhibitors for Mycobacterium tuberculosis ATP phosphoribosyl transferase (HisG) through virtual screening.
abstract: HisG is an ATP-phosphoribosyl transferase (ATPPRTase) that catalyzes the first step in the biosynthetic pathway for histidine. Among the enzymes in this pathway, only HisG represents a potential drug target for tuberculosis. Only a few inhibitors with limited potency for HisG are currently known. To discover more potent and diverse inhibitors, virtual screening was performed. The crystal structure of M. tuberculosis HisG has been solved and reveals a large, solvent-exposed active site with subsites for ATP and PRPP substrates. Two docking algorithms, GOLD and FLEXX, were used to screen two large libraries, Chembridge and NCI, containing over 500000 compounds combined. An initial subset of top-ranked compounds were selected and assayed, and seven were found to have enzyme inhibition activity at micromolar concentrations. Several of the hits contained a nitrobenzothiazole fragment, which was predicted to dock into the monophosphate-binding loop, and this binding mode was confirmed by crystallographic evidence. A secondary screen was performed to identify compounds with similar structures. Several of these also exhibited micromolar inhibition. Furthermore, two of the compounds showed bacteriocidal activity in a whole-cell assay against Mycobacterium smegmatis.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Yoonsang
authors.initials: Y
authors.lastname: Cho
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Ioerger
authors.forename: James C
authors.initials: JC
authors.lastname: Sacchettini
mesh_terms: D001276:ATP Phosphoribosyltransferase / Q000037:antagonists & inhibitors*; D000465:Algorithms; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000254:growth & development; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013499:Surface Properties
chemical_list: D001426:Bacterial Proteins; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D001276:ATP Phosphoribosyltransferase
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