Overview of the SAMPL5 host-guest challenge: Are we doing better?
Overview of the SAMPL5 host-guest challenge: Are we doing better?
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DOI：
10.1007/s10822-016-9974-4
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发表时间：
2017-01-01
影响因子：
3.5
通讯作者：
Gilson, Michael K.
中科院分区：
文献类型：
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作者：
Yin, Jian;Henriksen, Niel M.;Gilson, Michael K.
高精度地计算预测蛋白质-小分子结合亲和力的能力将通过消除对候选配体的反复试验和实验评估来加速药物发现并降低其成本。随着学术和工业团体致力于这一能力，对可用于严格测试新计算方法的数据集的需求持续存在。尽管蛋白质配基数据对于这一目的显然很重要，但它们的大小和复杂性使得获得良好收敛的结果和解决计算方法问题变得困难。主客体系统提供了一类有价值的替代测试用例，因为它们例证了非共价分子识别，但要小得多，也更简单。因此，主-客系统一直是前两轮SAMPL预测练习的一部分，它们也出现在本轮SAMPL5中。除了是盲目的，从而避免了在回溯性研究中可能出现的偏见，样本挑战的优点是将多个研究人员集中在一组共同的分子系统上，以便可以比较方法和交流想法。本文概述了SAMPL5的主客体成分，它集中在水溶液中的三种不同的宿主、两个辛酸和一个基于甘脲的分子夹以及两组不同的客体分子上。应用了一系列方法，包括用隐式溶剂模型计算电子结构；将经验力场与隐式溶剂模型相结合的方法；以及显式溶剂自由能模拟。最可靠的方法往往落在后一类，与之前几轮样本的结果一致，但准确性水平仍低于寻求可靠的计算机辅助药物设计。在力场精度、质子化平衡建模、电子结构方法和溶剂模型方面的进展为未来的改进提供了希望。
The ability to computationally predict protein-small molecule binding affinities with high accuracy would accelerate drug discovery and reduce its cost by eliminating rounds of trial-and-error synthesis and experimental evaluation of candidate ligands. As academic and industrial groups work toward this capability, there is an ongoing need for datasets that can be used to rigorously test new computational methods. Although protein-ligand data are clearly important for this purpose, their size and complexity make it difficult to obtain well-converged results and to troubleshoot computational methods. Host-guest systems offer a valuable alternative class of test cases, as they exemplify noncovalent molecular recognition but are far smaller and simpler. As a consequence, host-guest systems have been part of the prior two rounds of SAMPL prediction exercises, and they also figure in the present SAMPL5 round. In addition to being blinded, and thus avoiding biases that may arise in retrospective studies, the SAMPL challenges have the merit of focusing multiple researchers on a common set of molecular systems, so that methods may be compared and ideas exchanged. The present paper provides an overview of the host-guest component of SAMPL5, which centers on three different hosts, two octa-acids and a glycoluril-based molecular clip, and two different sets of guest molecules, in aqueous solution. A range of methods were applied, including electronic structure calculations with implicit solvent models; methods that combine empirical force fields with implicit solvent models; and explicit solvent free energy simulations. The most reliable methods tend to fall in the latter class, consistent with results in prior SAMPL rounds, but the level of accuracy is still below that sought for reliable computer-aided drug design. Advances in force field accuracy, modeling of protonation equilibria, electronic structure methods, and solvent models, hold promise for future improvements.