Dipartimento di Scienze dell'Ambiente e del Territorio, Università degli Studi di Milano-Bicocca, Milano, Italy.
J Comput Chem. 2011 Jan 15;32(1):81-98. doi: 10.1002/jcc.21601.
Ligand-protein docking is increasingly used in Drug Discovery. The initial limitations imposed by a reduced availability of target protein structures have been overcome by the use of theoretical models, especially those derived by homology modeling techniques. While this greatly extended the use of docking simulations, it also introduced the need for general and robust criteria to estimate the reliability of docking results given the model quality. To this end, a large-scale experiment was performed on a diverse set including experimental structures and homology models for a group of representative ligand-protein complexes. A wide spectrum of model quality was sampled using templates at different evolutionary distances and different strategies for target-template alignment and modeling. The obtained models were scored by a selection of the most used model quality indices. The binding geometries were generated using AutoDock, one of the most common docking programs. An important result of this study is that indeed quantitative and robust correlations exist between the accuracy of docking results and the model quality, especially in the binding site. Moreover, state-of-the-art indices for model quality assessment are already an effective tool for an a priori prediction of the accuracy of docking experiments in the context of groups of proteins with conserved structural characteristics.
配体-蛋白质对接在药物发现中越来越多地被使用。最初，由于目标蛋白质结构的可用性有限，因此受到限制，但通过使用理论模型，特别是通过同源建模技术获得的理论模型，这个问题得到了解决。虽然这极大地扩展了对接模拟的应用，但也需要一般的和稳健的标准来估计对接结果的可靠性，因为考虑到模型的质量。为此，在一组具有代表性的配体-蛋白质复合物中，进行了一项大规模的实验，该实验涵盖了不同的实验结构和同源模型。使用不同进化距离的模板和不同的目标-模板对齐和建模策略，对不同的模型质量进行了采样。通过选择最常用的模型质量指数对获得的模型进行了评分。使用 AutoDock 生成了结合几何形状，这是最常用的对接程序之一。这项研究的一个重要结果是，对接结果的准确性与模型质量之间确实存在定量和稳健的相关性，尤其是在结合位点。此外，用于模型质量评估的最先进的指标已经是一种有效的工具，可以在具有保守结构特征的蛋白质组中，对对接实验的准确性进行先验预测。
