De Novo Design of Boron-Based Peptidomimetics as Potent Inhibitors of Human ClpP in the Presence of Human ClpX.
De Novo Design of Boron-Based Peptidomimetics as Potent Inhibitors of Human ClpP in the Presence of Human ClpX.
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DOI：
10.1021/acs.jmedchem.9b00878
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发表时间：
2019-06
影响因子：
7.3
通讯作者：
Joanne Tan;Julie Grouleff;Y. Jitkova;D. Diaz;E. Griffith;Wenjie Shao;Anastasia F. Bogdanchikova;G. Poda;A. Schimmer;Richard E. Lee;A. Yudin
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文献类型：
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作者：
Joanne Tan;Julie Grouleff;Y. Jitkova;D. Diaz;E. Griffith;Wenjie Shao;Anastasia F. Bogdanchikova;G. Poda;A. Schimmer;Richard E. Lee;A. Yudin
由于硼具有调节酶功能的能力，因此引起了合成化学家和药物化学家的注意。最近，我们证明了含硼两性构筑块促进了生物活性氨基硼酸的发现。在这里，我们通过从头开始的文库设计和针对共价配体进行修改的虚拟筛选平台来增强这一能力。这项技术使我们能够快速设计和鉴定一系列α-氨基硼酸作为人类ClpXP的第一个抑制剂，它负责错误折叠蛋白质的降解。
Boronic acids have attracted the attention of synthetic and medicinal chemists due to boron's ability to modulate enzyme function. Recently, we demonstrated that boron-containing amphoteric building blocks facilitate the discovery of bioactive aminoboronic acids. Herein, we have augmented this capability with a de novo library design and a virtual screening platform modified for covalent ligands. This technique has allowed us to rapidly design and identify a series of α-aminoboronic acids as the first inhibitors of human ClpXP, which is responsible for the degradation of misfolded proteins.