Identification of small molecule inhibitors of PTPσ through an integrative virtual and biochemical approach.
Identification of small molecule inhibitors of PTPσ through an integrative virtual and biochemical approach.
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DOI：
10.1371/journal.pone.0050217
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
MacKeigan JP
中科院分区：
文献类型：
--
作者：
Martin KR;Narang P;Xu Y;Kauffman AL;Petit J;Xu HE;Meurice N;MacKeigan JP
PTPσ是一种双结构域受体型蛋白酪氨酸磷酸酶（PTP），具有重要的生理功能，是一种有吸引力的生物靶点。具体来说，PTPσ的缺失已被证明会引发许多细胞表型，包括脊髓损伤（SCI）后神经再生增强、培养癌细胞的化疗耐药性和过度活跃的自噬，这是一个对细胞存活和神经退行性疾病病理聚集物清除至关重要的过程。由于这些功能，调节PTPσ可以在各种情况下提供治疗价值。此外，一个小分子抑制剂将为识别PTPσ的细胞功能和底物提供实用价值。为了开发这样的分子，我们将硅模拟与体外磷酸酶测定相结合，以确定有效抑制PTPσ酶活性的化合物。重要的是，我们观察到PTPσ抑制经常是由溶液中化合物产生的氧化物种介导的，我们进一步优化了筛选条件以消除这种影响。我们发现了一种抑制PTPσ的化合物，其IC50为10µM，主要是不依赖氧化的。该化合物能很好地结合PTPσ在硅中的D1活性位点，表明它是一种竞争性抑制剂。该化合物将作为未来研究的支架结构，旨在建立PTPσ对相关PTPs的选择性。
PTPσ is a dual-domain receptor type protein tyrosine phosphatase (PTP) with physiologically important functions which render this enzyme an attractive biological target. Specifically, loss of PTPσ has been shown to elicit a number of cellular phenotypes including enhanced nerve regeneration following spinal cord injury (SCI), chemoresistance in cultured cancer cells, and hyperactive autophagy, a process critical to cell survival and the clearance of pathological aggregates in neurodegenerative diseases. Owing to these functions, modulation of PTPσ may provide therapeutic value in a variety of contexts. Furthermore, a small molecule inhibitor would provide utility in discerning the cellular functions and substrates of PTPσ. To develop such molecules, we combined in silico modeling with in vitro phosphatase assays to identify compounds which effectively inhibit the enzymatic activity of PTPσ. Importantly, we observed that PTPσ inhibition was frequently mediated by oxidative species generated by compounds in solution, and we further optimized screening conditions to eliminate this effect. We identified a compound that inhibits PTPσ with an IC50 of 10 µM in a manner that is primarily oxidation-independent. This compound favorably binds the D1 active site of PTPσ in silico, suggesting it functions as a competitive inhibitor. This compound will serve as a scaffold structure for future studies designed to build selectivity for PTPσ over related PTPs.
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影响因子：
2.7
作者：
Hu, Xin
通讯作者：
Hu, Xin
影响因子：
2.9
作者：
GUAN, KL;DIXON, JE
通讯作者：
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影响因子：
3.4
作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1007/s10969-007-9036-1
发表时间：
2007-09-01
期刊：
Journal of Structural and Functional Genomics
影响因子：
--
作者：
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通讯作者：
Burley, Stephen K.