It is frequently mentioned that QSARs have not generally lived up to expectations, especially in cases where high predictability is expected yet failed to deliver satisfactory results. Even though outliers can provide an increased opportunity in drug discovery research, outliers in SAR and QSAR can contort predictions and affect the accuracy if proper attention is not given. The percentages of outliers in QSARs have not changed appreciably over the last decade. In our previous studies, we suggested two possible sources of outliers in SAR and QSAR. In this paper, we suggest an additional possible source of outliers in QSAR. We presented several literature examples that show one or more water molecules that play a critical role in protein–ligand binding interactions as observed in their crystal structures. These examples illustrate that failing to account for the effects of water molecules in protein–ligand interactions could mislead interpretation and possibly yield outliers in SAR and QSAR. Examples include cases where QSAR, considering the role of water molecules in protein–ligand crystal structures, provided deeper insight into the understanding and interpretation of the developed QSAR.

人们经常提到 QSAR 通常没有达到预期，特别是在预期具有高可预测性但未能提供令人满意结果的情况下。尽管异常值可以为药物发现研究提供更多机会，但如果不给予适当关注，SAR 和 QSAR 中的异常值会扭曲预测并影响准确性。在过去十年中，QSAR 中异常值的百分比没有明显变化。在我们之前的研究中，我们提出了 SAR 和 QSAR 中两种可能的异常值来源。在本文中，我们提出了 QSAR 中一个额外的可能异常值来源。我们提供了几个文献示例，这些示例显示一个或多个水分子在其晶体结构中观察到的蛋白质-配体结合相互作用中起关键作用。这些例子说明，未能考虑水分子在蛋白质-配体相互作用中的影响可能会误导解释，并可能在 SAR 和 QSAR 中产生异常值。例子包括 QSAR，考虑到水分子在蛋白质 - 配体晶体结构中的作用，提供了对开发的 QSAR 的理解和解释的更深入的了解。