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 activit

SUBMITTER: Cho Y 

PROVIDER: S-EPMC2610488 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature