In silico modeling of protein tyrosine phosphatase 1B inhibitors with cellular activity
In silico modeling of protein tyrosine phosphatase 1B inhibitors with cellular activity
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DOI：
10.1016/j.bmcl.2006.09.010
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发表时间：
2006-12-15
影响因子：
2.7
通讯作者：
Hu, Xin
中科院分区：
文献类型：
--
作者：
Hu, Xin
蛋白酪氨酸磷酸酶1B（PTP1B）是治疗2型糖尿病和肥胖症的潜在药物靶点。PTP1B抑制剂作为治疗剂的设计主要由于其差的细胞渗透性和口服生物利用度而受到阻碍。在本研究中，我们研究了PTP1B抑制剂的细胞活性与使用经典VolSurf分析的3D结构的关系。基于VolSurf描述符的PTP1B抑制剂的一组80种化合物的模型，其中一半显示细胞活性，使用主成分分析（PCA）方法进行了分析。用该模型对40个PTP1B抑制剂的细胞活性进行了预测，得到了满意的结果。进一步的偏最小二乘（PLS）分析揭示了有用的信息的Volsurf描述符的行为在预测PTP1B抑制剂的细胞渗透性和药代动力学特性。计算机模拟ADME研究为开发有效的PTP1B抑制剂作为候选药物提供了一种有价值的工具。(c)2006爱思唯尔有限公司保留所有权利。
Protein tyrosine phosphatase 1B (PTP1B) is a potential drug target for the treatment of Type 2 diabetes and obesity. The design of PTP1B inhibitors as therapeutic agents has been hampered mostly owing to their poor cell permeability and oral bioavailability. In the present study, we investigated the cellular activity of PTP1B inhibitors in relation to the 3D structure using classical VolSurf analysis. A model based on the VolSurf descriptors for a set of 80 compounds of PTP1B inhibitors, half of which display cellular activity, was analyzed using the principal components analysis (PCA) approach. The PCA model was applied to predict the cellular activities of an external data set of 40 PTP1B inhibitors and satisfactory results were obtained. Further partial least squares (PLS) analysis revealed useful information about the behavior of the Volsurf descriptors in predicting the cell permeability and pharmacokinetic properties of PTP1B inhibitors. In silico ADME studies provide a valuable tool in the development of effective PTP1B inhibitors as drug candidates. (c) 2006 Elsevier Ltd. All rights reserved.