Fragment-based discovery of selective inhibitors of the Mycobacterium tuberculosis protein tyrosine phosphatase PtpA.
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.
Rawls
Katherine A
KA
Department of Chemistry, University of California, Berkeley, CA 94720 1460, USA.
Lang
P Therese
PT
Takeuchi
Jun
J
Imamura
Shinichi
S
Baguley
Tyler D
TD
Grundner
Christoph
C
Alber
Tom
T
Ellman
Jonathan A
JA
D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*
D000813:Anilides; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; C414465:MptpA protein, Mycobacterium tuberculosis; C034595:benzanilide; D017027:Protein Tyrosine Phosphatases