Comparative Modeling: The State of the Art and Protein Drug Target Structure Prediction
Comparative Modeling: The State of the Art and Protein Drug Target Structure Prediction
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DOI：
10.2174/138620711795767811
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发表时间：
2011-07-01
影响因子：
1.8
通讯作者：
Capriotti, Emidio
中科院分区：
文献类型：
--
作者：
Liu, Tianyun;Tang, Grace W.;Capriotti, Emidio
计算蛋白质结构预测的目标是提供分辨率与实验结果相当的三维（3D）结构。比较建模是基于序列与同源结构的相似性来预测蛋白质的三维结构，是最准确的结构预测计算方法。在过去的二十年中，比较建模方法取得了重大进展。利用蛋白质数据库（protein Data Bank）中存储的大量蛋白质结构（约65,000个），自动预测管道正在为尚未通过实验确定结构的序列生成大量模型（约190万个）。准确的模型适用于广泛的应用，如预测蛋白质结合位点，预测蛋白质突变的影响，以及结构引导的虚拟筛选。特别是，比较建模使基于结构的药物设计能够针对具有未知结构的蛋白质靶点。本文综述了比较建模的理论基础，现有的自动建模方法和数据库，以及评估预测结构精度的算法。最后，我们讨论了相关的应用在预测重要的药物靶蛋白，重点是G蛋白偶联受体（GPCR）和蛋白激酶家族。
The goal of computational protein structure prediction is to provide three-dimensional (3D) structures with resolution comparable to experimental results. Comparative modeling, which predicts the 3D structure of a protein based on its sequence similarity to homologous structures, is the most accurate computational method for structure prediction. In the last two decades, significant progress has been made on comparative modeling methods. Using the large number of protein structures deposited in the Protein Data Bank (similar to 65,000), automatic prediction pipelines are generating a tremendous number of models (similar to 1.9 million) for sequences whose structures have not been experimentally determined. Accurate models are suitable for a wide range of applications, such as prediction of protein binding sites, prediction of the effect of protein mutations, and structure-guided virtual screening. In particular, comparative modeling has enabled structure-based drug design against protein targets with unknown structures. In this review, we describe the theoretical basis of comparative modeling, the available automatic methods and databases, and the algorithms to evaluate the accuracy of predicted structures. Finally, we discuss relevant applications in the prediction of important drug target proteins, focusing on the G protein-coupled receptor (GPCR) and protein kinase families.