The Mycobacterium tuberculosis extracellular zinc metalloprotease 1 (Zmp1) has been proposed to play a key role in phagosome maturation and to enhance the survival of Mycobacterium tuberculosis in the host. Consequently, small molecule inhibitors of Zmp1 are of pivotal importance as a tool to better understand the pathogenicity of Zmp1 and as lead candidates for pharmacological intervention. Here we combined in silico structure-based inhibitor design with biochemical studies to discover and characterize the first potent competitive Zmp1 inhibitor showing a Ki of 94nM and a high selectivity for Zmp1 with respect to human Neprilysin.
Mori, M., Moraca, F., Deodato, D., Ferraris, D.M., Selchow, P., Sander, P., et al. (2014). Discovery of the first potent and selective Mycobacterium tuberculosis Zmp1 inhibitor. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 24(11), 2508-2511 [10.1016/j.bmcl.2014.04.004].
Discovery of the first potent and selective Mycobacterium tuberculosis Zmp1 inhibitor
Mori, Mattia;Moraca, Francesca;Deodato, Davide;Rizzi, M.;Botta, Maurizio
2014-01-01
Abstract
The Mycobacterium tuberculosis extracellular zinc metalloprotease 1 (Zmp1) has been proposed to play a key role in phagosome maturation and to enhance the survival of Mycobacterium tuberculosis in the host. Consequently, small molecule inhibitors of Zmp1 are of pivotal importance as a tool to better understand the pathogenicity of Zmp1 and as lead candidates for pharmacological intervention. Here we combined in silico structure-based inhibitor design with biochemical studies to discover and characterize the first potent competitive Zmp1 inhibitor showing a Ki of 94nM and a high selectivity for Zmp1 with respect to human Neprilysin.
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https://hdl.handle.net/11365/46087
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