Is It Reliable to Take the Molecular Docking Top Scoring Position as the Best Solution without Considering Available Structural Data?
Is It Reliable to Take the Molecular Docking Top Scoring Position as the Best Solution without Considering Available Structural Data?
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DOI：
10.3390/molecules23051038
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发表时间：
2018-04-28
期刊：
影响因子：
--
通讯作者：
Caballero J
中科院分区：
文献类型：
--
作者：
Ramírez D;Caballero J
分子对接是研究有机分子与生物大分子相互作用最常用的计算方法。在这种情况下，对接允许预测受体结合位点内配体的优选姿势。然而，尽管广泛接受的选择标准是最佳姿势对应于最佳能量分数，但选择“最佳”解决方案并不是一项微不足道的任务。在这里，几个刚性目标对接方法在相同的数据集上进行了评估，就其再现晶体结合方向的能力，以测试最佳能量分数是否是选择最佳解决方案的可靠标准。为此，进行了两个实验：（A）通过在其自身的晶体结构受体中进行配体的对接（定义为自对接）来重建配体-受体复合物，和（B）通过在含有其它配体的晶体结构受体中进行配体的对接（定义为交叉对接）来重建配体-受体复合物。均方根偏差（RMSD）被用来评估如何不同的对接方向是从相应的共结晶的姿势相同的配体分子。我们发现，对接得分函数是能够预测晶体结合方向，但最好的排名解决方案，根据对接能量并不总是再现实验结合方向的姿势。这发生在实现自对接时，但在交叉对接中至关重要。考虑到对接通常用于预测目的，在交叉对接实验中，我们的结果表明，最佳能量分数不是一个可靠的标准，以选择最佳的解决方案，在常见的对接应用。强烈建议根据评分函数沿着以及类似物配体描述的其他结构标准选择最佳对接溶液，以确保选择正确的对接溶液。
Molecular docking is the most frequently used computational method for studying the interactions between organic molecules and biological macromolecules. In this context, docking allows predicting the preferred pose of a ligand inside a receptor binding site. However, the selection of the “best” solution is not a trivial task, despite the widely accepted selection criterion that the best pose corresponds to the best energy score. Here, several rigid-target docking methods were evaluated on the same dataset with respect to their ability to reproduce crystallographic binding orientations, to test if the best energy score is a reliable criterion for selecting the best solution. For this, two experiments were performed: (A) to reconstruct the ligand-receptor complex by performing docking of the ligand in its own crystal structure receptor (defined as self-docking), and (B) to reconstruct the ligand-receptor complex by performing docking of the ligand in a crystal structure receptor that contains other ligand (defined as cross-docking). Root-mean square deviation (RMSD) was used to evaluate how different the obtained docking orientation is from the corresponding co-crystallized pose of the same ligand molecule. We found that docking score function is capable of predicting crystallographic binding orientations, but the best ranked solution according to the docking energy is not always the pose that reproduces the experimental binding orientation. This happened when self-docking was achieved, but it was critical in cross-docking. Taking into account that docking is typically used with predictive purposes, during cross-docking experiments, our results indicate that the best energy score is not a reliable criterion to select the best solution in common docking applications. It is strongly recommended to choose the best docking solution according to the scoring function along with additional structural criteria described for analogue ligands to assure the selection of a correct docking solution.
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