CADRE-SS, an in Silico Tool for Predicting Skin Sensitization Potential Based on Modeling of Molecular Interactions
CADRE-SS, an in Silico Tool for Predicting Skin Sensitization Potential Based on Modeling of Molecular Interactions
复制标题
DOI：
10.1021/acs.chemrestox.5b00392
复制
发表时间：
2016-01-01
影响因子：
4.1
通讯作者：
Voutchkova-Kostal, Adelina
中科院分区：
文献类型：
--
作者：
Kostal, Jakub;Voutchkova-Kostal, Adelina
使用计算机模型来准确预测毒性结果被认为是一项重大挑战。然而，在过去十年中机械毒理学的进步和计算资源的指数增长的支持下，最先进的计算化学技术现在可以被纳入预测模型。CADRE(计算机辅助发现和重新设计)平台依赖于分子相互作用的量子力学建模，分子相互作用代表了毒性途径中的关键生化触发因素。在这里，我们提出了一个外部验证实践的CADRE-SS，一种变种开发，以预测皮肤致敏潜力的商业化学品。CADRE-SS是一种混合模型，它使用蒙特卡罗模拟来评估皮肤的渗透性，通过专家规则分配分子中的反应中心和可能的生物转化，并通过量子力学模型来确定与皮肤蛋白质的反应性。结果令人满意，实验值和预测值之间总体上有很好的一致性，达到93%。与这一终点可用的其他工具产生的性能指标进行比较表明，CADRE-SS在化学品的第一轮筛选中具有明显的优势，在立法项目允许的情况下，可以用作动物试验的电子替代方法。
Using computer models to accurately predict toxicity outcomes is considered to be a major challenge. However, state-of-the-art computational chemistry techniques can now be incorporated in predictive models, supported by advances in mechanistic toxicology and the exponential growth of computing resources witnessed over the past decade. The CADRE (Computer-Aided Discovery and REdesign) platform relies on quantum-mechanical modeling of molecular interactions that represent key biochemical triggers in toxicity pathways. Here, we present an external validation exercise for CADRE-SS, a variant developed to predict the skin sensitization potential of commercial chemicals. CADRE-SS is a hybrid model that evaluates skin permeability using Monte Carlo simulations, assigns reactive centers in a molecule and possible biotransformations via expert rules, and determines reactivity with skin proteins via quantum-mechanical modeling. The results were promising with an overall very good concordance of 93% between experimental and predicted values. Comparison to performance metrics yielded by other tools available for this endpoint suggests that CADRE-SS offers distinct advantages for first-round screenings of chemicals and could be used as an in silico alternative to animal tests where permissible by legislative programs.