Docking Ligands into Flexible and Solvated Macromolecules. 4. Are Popular Scoring Functions Accurate for this Class of Proteins?
Docking Ligands into Flexible and Solvated Macromolecules. 4. Are Popular Scoring Functions Accurate for this Class of Proteins?
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DOI：
10.1021/ci8004308
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发表时间：
2009-06-01
影响因子：
5.6
通讯作者：
Moitessier, Nicolas
中科院分区：
文献类型：
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作者：
Englebienne, Pablo;Moitessier, Nicolas
在我们之前的报告中，我们研究了蛋白质灵活性和水分子的存在对主要对接程序的姿态预测精度的影响。为了完成这些调查，我们在此报告了这两个方面对评分函数准确性的影响的研究。为此，我们开发了两组由配体与多种蛋白质交叉对接或共结晶组成的蛋白质/配体复合物，具有桥接水分子和展示蛋白质灵活性的特点。我们努力降低所选配体的分子量与其结合亲和力之间的相关性，这是先前报道的一些基准集的主要偏差。使用这些集合，评估了18个可用的评分函数预测结合亲和力的准确性，并根据它们对共结晶蛋白质的亲和力对化合物进行排序。本研究证实Xscore、GlideScore、DrugScore（CSD）、GoldScore、PLP1、ChemScore、RankScore和eHiTS评分功能具有良好且相似的准确性。我们接下来的研究表明，当没有提供正确的蛋白质构象时，大多数评估的评分功能的准确性要低得多。本研究还表明，考虑水分子评分对准确性影响不大。最后，这项工作揭示了评分函数之间的高度相关性和人们可以从共识评分中期望的准确性的低增长。
In our previous report, we investigated the impact of protein flexibility and the presence of water molecules on the pose-prediction accuracy of major docking programs. To complete these investigations, we report herein a study of the impact of these two aspects on the accuracy of scoring functions. To this effect, we developed two sets of protein/ligand complexes made up of ligands cross-docked or cocrystallized with a large variety of proteins, featuring bridging water molecules and demonstrating protein flexibility. Efforts were made to reduce the correlation between the molecular weights of the selected ligands and their binding affinities, a major bias in some previously reported benchmark sets. Using these sets, 18 available scoring functions have been assessed for their accuracy to predict binding affinities and to rank-order compounds by their affinity to cocrystallized proteins. This study confirmed the good and similar accuracy of Xscore, GlideScore, DrugScore(CSD), GoldScore, PLP1, ChemScore, RankScore, and the eHiTS scoring function. Our next investigations demonstrated that most of the assessed scoring functions were much less accurate when the correct protein conformation was not provided. This study also revealed that considering the water molecules for scoring does not greatly affect the accuracy. Finally, this work sheds light on the high correlation between scoring functions and the poor increase in accuracy one can expect from consensus scoring.