Inhibition studies with rationally designed inhibitors of the human low molecular weight protein tyrosine phosphatase.
Inhibition studies with rationally designed inhibitors of the human low molecular weight protein tyrosine phosphatase.
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DOI：
10.1016/j.bmc.2004.01.042
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发表时间：
2004-04
影响因子：
3.5
通讯作者：
Adam P. R. Zabell;Steven J. Corden;P. Helquist;C. Stauffacher;O. Wiest
中科院分区：
文献类型：
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作者：
Adam P. R. Zabell;Steven J. Corden;P. Helquist;C. Stauffacher;O. Wiest
人低分子量蛋白酪氨酸磷酸酶(HCPTP)在多种细胞中以两种异构体的形式广泛表达，可能参与调节上皮性肿瘤的转移。根据已知的其他低分子量PTP的X射线晶体结构，提出了HCPTP-B异构体的同源模型。两种异构体结构的比较表明了开发HCPTP异构体特异性抑制剂的可能性。用CHARMM进行了分子动力学模拟，研究了已知腺嘌呤效应器与磷酸盐在两种异构体活性部位的结合模式。这一分析导致了基于氮杂环部分的初始先导化合物的设计，然后也进行了计算评估。这些模拟的比较表明在吲哚上需要一个膦酸基，并提供了对抑制剂结合模式的洞察。已经合成了结构与阿扎因多尔不同程度相似的化合物，并测试了每种异构体的抑制作用。用AutoDock程序对这些分子体系进行了研究，并与动力学和显式模拟进行了比较，以验证AutoDock作为潜在抑制剂的筛选工具。实验发现有两种化合物具有亚毫米级的抑制作用，但其中一种化合物的较大溶解度加强了在进行计算分析的同时进行实验测试的必要性。
The human low molecular weight protein tyrosine phosphatase (HCPTP) is ubiquitously expressed as two isoforms in a wide range of human cells and may be involved in regulating the metastatic nature of epithelial tumors. A homology model is presented for the HCPTP-B isoform based on known X-ray crystal structures of other low molecular weight PTPs. A comparison of the two isoform structures indicates the possibility of developing isoform-specific inhibitors of HCPTP. Molecular dynamics simulations with CHARMM have been used to study the binding modes of the known adenine effector and phosphate in the active site of both isoforms. This analysis led to the design of the initial lead compound, based on an azaindole ring moiety, which was then also evaluated computationally. A comparison of these simulations indicates the need for a phosphonate group on the indole and provides insight into inhibitor binding modes. Compounds with varying degrees of structural similarity to the azaindole have been synthesized and tested for inhibition with each isoform. These molecular systems were examined with the program AutoDock, and comparisons made with the kinetics and the explicit simulations to validate AutoDock as a screening tool for potential inhibitors. Two compounds were experimentally found to have sub-millimolar inhibition, but the greater solubility of one reinforces the need for experimental testing alongside computational analysis.