Xenobiotic electrophiles can form covalent adducts that may impair protein function, damage DNA, and may lead a range of adverse effects. Cumulative neurotoxicity is one adverse effect that has been linked to covalent protein binding as a Molecular Initiating Event (MIE). This paper describes a mechanistic in silico chemical screening approach for neurotoxicity based on Hard and Soft Acids and Bases (HSAB) theory. We evaluated the applicability of HSAB-based electrophilicity screening protocol for neurotoxicity on 19 positive and 19 negative reference chemicals. These reference chemicals were identified from the literature, using available information on mechanisms of neurotoxicity whenever possible. In silico screening was based on structural alerts for protein binding motifs and electrophilicity index in the range of known neurotoxicants. The approach demonstrated both a high positive prediction rate (82-90 %) and specificity (90 %). The overall sensitivity was relatively lower (47 %). However, when predicting the toxicity of chemicals known or suspected of acting via non-specific adduct formation mechanism, the HSAB approach identified 7/8 (sensitivity 88 %) of positive control chemicals correctly. Consequently, the HSAB-based screening is a promising approach of identifying possible neurotoxins with adduct formation molecular initiating events. While the approach must be expanded over time to capture a wider range of MIEs involved in neurotoxicity, the mechanistic nature of the screen allows users to flag chemicals for possible adduct formation MIEs. Thus, the HSAB based toxicity screening is a promising strategy for toxicity assessment and chemical prioritization in neurotoxicology and other health endpoints that involve adduct formation.

中文翻译：

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硬和软，酸和碱（HSAB）理论的应用作为预测累积神经毒性的方法。

异种亲电试剂会形成共价加合物，可能损害蛋白质功能，破坏DNA并可能导致一系列不利影响。累积神经毒性是一种与共价蛋白结合相关的不良反应，是一种分子引发事件（MIE）。本文介绍了一种基于硬酸和软酸和碱（HSAB）理论的机械性计算机化学化学方法对神经毒性的筛选方法。我们评估了基于HSAB的亲电筛选方案对19种阳性和19种阴性参考化学药品的神经毒性的适用性。这些参考化学品是从文献中识别出来的，并尽可能使用有关神经毒性机制的可用信息。电子计算机筛查是基于结构警报，了解已知神经毒性物质范围内的蛋白结合基序和亲电指数。该方法显示出较高的阳性预测率（82-90％）和特异性（90％）。总体灵敏度相对较低（47％）。但是，在预测已知或怀疑通过非特异性加合物形成机理起作用的化学药品的毒性时，HSAB方法可正确识别出7/8（敏感性88％）阳性对照化学药品。因此，基于HSAB的筛选是一种有可能鉴定具有加合物形成分子引发事件的神经毒素的方法。尽管必须随时间扩展方法以捕获涉及神经毒性的更广泛的MIE，但筛查的机械性质允许用户标记化学药品，以了解可能形成加合物的MIE。从而，