Double click reaction for the acquisition of a highly potent and selective mPTPB inhibitor |
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Authors: | He Rongjun Yu Zhihong He Yantao Zeng Li-Fan Xu Jie Wu Li Gunawan Andrea M Wang Lina Jiang Zhong-Xing Zhang Zhong-Yin |
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Affiliation: | Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, 46202, USA. |
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Abstract: | 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 Ki 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. |
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Keywords: | Click chemistry drug design protein tyrosine phosphatases inhibitors tuberculosis |
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