The interprotein scoring noises in glide docking scores
The interprotein scoring noises in glide docking scores
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DOI：
10.1002/prot.23173
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发表时间：
2012-01
期刊：
影响因子：
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通讯作者：
Wei Wang;Xiaoping Zhou;Wanlin He;Yi Fan;Yuzong Chen;Xin Chen
中科院分区：
文献类型：
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作者：
Wei Wang;Xiaoping Zhou;Wanlin He;Yi Fan;Yuzong Chen;Xin Chen
小分子药物很少有足够的选择性，仅与其指定的靶标相互作用。非预期的“脱靶”相互作用通常会导致副作用，但也会意外地导致新的治疗用途。因此，鉴定化合物的脱靶点对于评价其开发潜力具有重要价值。在计算生物学中，“反向对接”策略已经被引入到预测化合物的靶点中，该策略使用化合物来虚拟筛选蛋白质库，在“正常”对接筛选中逆转诱饵和猎物。本研究表明，在反向对接，额外的优化的评分函数可能有助于提高目标预测精度。在Glide评分的案例研究中，我们发现在58个复合物的库中，只有57%的配体-蛋白质关系可以被正确识别，这些复合物的晶体结合构象都能够准确再现。这可能是特定蛋白质评分不断高估或低估的结果。换句话说，在Glide评分中存在蛋白间噪音。引入基于蛋白质特征的校正项将目标预测准确度提高了27%（57-72%）。我们希望，对Glide评分的集中讨论将促使进一步努力在所有对接评分中表征和标准化这种类型的蛋白质间噪声，以便通过反向对接策略实现更好的靶点预测准确性。Proteins 2012; © 2011 Wiley Periodicals，Inc.
Small molecule drugs are rarely selective enough to interact solely with their designated targets. Unintended “off‐target” interactions often lead to side effects, but also serendipitously lead to new therapeutic uses. Identification of the off‐targets of a compound is therefore of significant value to the evaluation of its developmental potential. In computational biology, the strategy of “reverse docking” has been introduced to predict the targets of a compound, which uses a compound to virtually screen a library of proteins, reversing the bait and prey in “normal” docking screenings. The present study shows that, in reverse docking, additional optimization of the scoring function may help to improve the target prediction accuracy. In a case study with the Glide scores, we found that only 57% of the ligand–protein relationships could be correctly identified in a library of 58 complexes whose crystal binding conformations were all able to be accurately reproduced. This was likely a result of the constant over‐ or under‐estimation of the scores for specific proteins. In other words, there were interprotein noises in the Glide scores. Introducing a correction term based on protein characteristics improved the target‐prediction accuracy by 27% (57–72%). It is our hope that this focused discussion on the Glide scores would invite further efforts to characterize and normalize this type of interprotein noises in all docking scores, so that better target prediction accuracy can be achieved with the strategy of reverse docking. Proteins 2012; © 2011 Wiley Periodicals, Inc.