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Fragment-based discovery of selective inhibitors of the Mycobacterium tuberculosis protein tyrosine phosphatase PtpA.

ABSTRACT: The development of low muM inhibitors of the Mycobacterium tuberculosis phosphatase PtpA is reported. The most potent of these inhibitors (K(i)=1.4+/-0.3 microM) was found to be selective when tested against a panel of human tyrosine and dual-specificity phosphatases (11-fold vs the highly homologous HCPtpA, and >70-fold vs all others tested). Modeling the inhibitor-PtpA complexes explained the structure-activity relationships observed in vitro and revealed further possibilities for compound development.

SUBMITTER: Rawls KA

PROVIDER: S-EPMC2801607 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Fragment-based discovery of selective inhibitors of the Mycobacterium tuberculosis protein tyrosine phosphatase PtpA.

Rawls Katherine A KA Lang P Therese PT Takeuchi Jun J Imamura Shinichi S Baguley Tyler D TD Grundner Christoph C Alber Tom T Ellman Jonathan A JA

Bioorganic & medicinal chemistry letters 20091025 24

The development of low muM inhibitors of the Mycobacterium tuberculosis phosphatase PtpA is reported. The most potent of these inhibitors (K(i)=1.4+/-0.3 microM) was found to be selective when tested against a panel of human tyrosine and dual-specificity phosphatases (11-fold vs the highly homologous HCPtpA, and >70-fold vs all others tested). Modeling the inhibitor-PtpA complexes explained the structure-activity relationships observed in vitro and revealed further possibilities for compound dev ...[more]

PMID: 19889539

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