Double 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 high potency and selectivity of the lead compound and reveals an unusual binding mode, which may guide further optimization effort.
He
Rongjun
R
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, 46202, USA.
Yu
Zhihong
Z
He
Yantao
Y
Zeng
Li-Fan
LF
Xu
Jie
J
Wu
Li
L
Gunawan
Andrea M
AM
Wang
Lina
L
Jiang
Zhong-Xing
ZX
Zhang
Zhong-Yin
ZY
D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057930:Click Chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; C414465:MptpA protein, Mycobacterium tuberculosis; D017027:Protein Tyrosine Phosphatases