biostudies-literatureHe RNCI NIH HHS2051-6https://www.ebi.ac.uk/biostudies/studies/S-EPMC3117672biostudies-literatureUnknown5(12)Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), is a major worldwide threat to public health. Mycobacterium protein tyrosine phosphatase B (mPTPB) is a virulent phosphatase secreted by Mtb, which is essential for the survival and persistence of the bacterium in the host. Consequently, small-molecule inhibitors of mPTPB are expected to serve as anti-TB agents with a novel mode of action. Herein, we report the discovery of highly potent and selective mPTPB inhibitors using a novel, double Click chemistry strategy. The most potent mPTPB inhibitor from this approach possesses a K(i) value of 160 nM and a >25-fold selectivity for mPTPB over 19 other protein tyrosine phosphatases (PTBs). Molecular docking study of the enzyme-inhibitor complex provides a rationale for the ChemMedChemDouble click reaction for the acquisition of a highly potent and selective mPTPB inhibitor.PMC3117672R01 CA126937CA69202R01 CA069202CA126937Zeng LFWu LHe YGunawan AMZhang ZYJiang ZXYu ZHe RXu JWang LfalseDouble click reaction for the acquisition of a highly potent and selective mPTPB inhibitor.Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), is a major worldwide threat to public health. Mycobacterium protein tyrosine phosphatase B (mPTPB) is a virulent phosphatase secreted by Mtb, which is essential for the survival and persistence of the bacterium in the host. Consequently, small-molecule inhibitors of mPTPB are expected to serve as anti-TB agents with a novel mode of action. Herein, we report the discovery of highly potent and selective mPTPB inhibitors using a novel, double Click chemistry strategy. The most potent mPTPB inhibitor from this approach possesses a K(i) value of 160 nM and a >25-fold selectivity for mPTPB over 19 other protein tyrosine phosphatases (PTBs). Molecular docking study of the enzyme-inhibitor complex provides a rationale for the 2010-01-01T00:00:00Z2010 Dec2026-04-30T22:28:17.265Z2026-04-07T16:22:48.713ZS-EPMC31176722095771810.1002/cmdc.201000348