Structural alerts are a simple and easy way to identify toxic compounds being widely used in environmental toxicology research and drug discovery. With the emergence of big data techniques in recent years and their applications in chemistry and toxicology, computational approaches have become a promising method to identify structural alerts. In this Review, we describe the recent progress in computational methods for identification of structural alerts and their applications in toxicology. Two major computational approaches, namely frequency analysis and interpretable machine learning models, are reviewed. Recent studies have shown that both approaches are superior to expert systems with respect to predictive capability. Methodologies for defining the applicability domain of such approaches are also reviewed, with their importance stemming from their ability to not only improve the predictive performance of structural alert models but also ensure the confidence of a prediction. In addition to toxicity prediction, structural alerts could be also used to explain quantitative structure–activity relationship models and guide lead optimization in drug discovery. Nevertheless, there are still some challenges to be solved, such as how to address the co-existence of several structural alerts in one molecule, how to directly compare computationally derived structural alerts with expert systems, and how to explore new mechanisms of toxicity.

中文翻译：

---

识别结构警报的计算方法及其在环境毒理学和药物发现中的应用。

结构警报是一种简单易行的方法，可以识别在环境毒理学研究和药物发现中广泛使用的有毒化合物。随着近年来大数据技术的出现及其在化学和毒理学中的应用，计算方法已成为识别结构警报的一种有前途的方法。在这篇综述中，我们描述了用于识别结构警报的计算方法及其在毒理学中的应用的最新进展。审查了两种主要的计算方法，即频率分析和可解释的机器学习模型。最近的研究表明，在预测能力方面，这两种方法均优于专家系统。还回顾了定义此类方法的适用范围的方法，它们的重要性源于它们不仅能够改善结构警报模型的预测性能，而且还能确保预测的可信度。除了毒性预测之外，结构警报还可以用于解释定量的构效关系模型，并指导药物发现中的前导优化。然而，仍然存在一些难题需要解决，例如如何解决一个分子中几种结构警报的共存，如何直接将计算得出的结构警报与专家系统进行比较以及如何探索毒性的新机制。结构警报还可用于解释定量的结构-活性关系模型，并指导药物发现中的线索优化。然而，仍然存在一些难题需要解决，例如如何解决一个分子中几种结构警报的共存，如何直接将计算得出的结构警报与专家系统进行比较以及如何探索毒性的新机制。结构警报还可用于解释定量的结构-活性关系模型，并指导药物发现中的线索优化。然而，仍然存在一些难题需要解决，例如如何解决一个分子中几种结构警报的共存，如何直接将计算得出的结构警报与专家系统进行比较以及如何探索毒性的新机制。