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[摘要]：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, contg. over 500000 compds. combined. An initial subset of top-ranked compds. were selected and assayed, and seven were found to have enzyme inhibition activity at micromolar concns. 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 crystallog. evidence. A secondary screen was performed to identify compds. with similar structures. Several of these also exhibited micromolar inhibition. Furthermore, two of the compds. showed bacteriocidal activity in a whole-cell assay against Mycobacterium smegmatis. |
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