School of Forestry and Environmental Studies, Yale University, New Haven, CT, 06511, United States.
Department of Anesthesiology, Montefiore Medical Center, Albert Einstein College of Medicine, 111 E. 210th St, Bronx, NY, 10467, United States.
Neurotoxicology. 2020 Jul;79:95-103. doi: 10.1016/j.neuro.2020.04.009. Epub 2020 May 5.
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.
外源性亲电物可形成可能损害蛋白质功能、破坏 DNA，并可能导致一系列不良反应的共价加合物。累积性神经毒性是与共价蛋白质结合作为分子起始事件 (MIE) 相关的一种不良反应。本文描述了一种基于软硬酸碱 (HSAB) 理论的机制计算化学神经毒性筛选方法。我们评估了基于 HSAB 的亲电性筛选方案对 19 种阳性和 19 种阴性参考化学物质神经毒性的适用性。这些参考化学物质是根据文献中关于神经毒性机制的可用信息从文献中确定的，只要有可能。基于结构的蛋白质结合基序和已知神经毒物范围内的亲电性指数的计算筛选。该方法表现出较高的阳性预测率 (82-90%) 和特异性 (90%)。总体敏感性相对较低 (47%)。然而，当预测已知或疑似通过非特异性加合物形成机制作用的化学物质的毒性时，HSAB 方法正确识别了 7/8(敏感性 88%)的阳性对照化学物质。因此，基于 HSAB 的筛选是一种很有前途的方法，可以识别具有加合物形成分子起始事件的可能神经毒物。虽然该方法必须随着时间的推移不断扩展，以捕捉更广泛的神经毒性相关 MIE，但该筛选的机制性质允许用户标记可能发生加合物形成 MIE 的化学物质。因此，基于 HSAB 的毒性筛选是神经毒理学和其他涉及加合物形成的健康终点的毒性评估和化学优先排序的有前途的策略。
