通过考虑生物激活和作用模式来完善和加强基于SAR的阅读
Gang Yan1, Jane Rose1, Corie Ellison1
1Global Product Stewardship, The Procter & Gamble Company, 8700 Mason Montgomery Rd., Mason, Ohio 45040, United States.
Chemical research in toxicology
|August 18, 2023
概括
通过考虑化学作用机制 (MOA),改进了结构-活性关系 (SAR) 阅读. 了解代谢途径和"活动悬崖"可以提高对缺乏数据的物质化学毒性预测的准确性.
科学领域:
- 毒理学和化学信息学
- 计算毒理学计算毒理学
- 化学安全评估 化学安全评估
背景情况:
- 基于结构-活性关系 (SAR) 的交叉阅读使用类似化学品的数据来评估数据较差的化合物的安全性.
- 目前的方法通常严重依赖于定量结构相似性,这可能无法准确预测毒性.
- 新兴的机械学数据为化学行为和潜在的毒性提供了更深入的见解.
研究的目的:
- 研究如何结合机械数据,如作用模式 (MOA) 和代谢途径,可以改进基于SAR的交叉读取.
- 为了确定由于影响新陈代谢的轻微结构变化而表现出显著毒性变化的化学品类.
- 为了提高模拟选择的准确性和可靠性,以及阅读交叉中的适用性评估.
主要方法:
- 确定具有"活动悬崖"的化学品类,其中微小的结构变化会改变代谢和毒性.
- 基于SAR的基于不同化学品类别和毒性终点的阅读交叉案例研究的分析.
- 通过整合MOA和反应性代谢物形成途径来评估模拟的适用性.
主要成果:
- 证明纯粹基于结构的相似性可能不足以准确地预测阅读的毒性.
- 突出显示了特定的化学序列,其中代谢和生物活化途径的改变显著影响了毒性.
- 案例研究证实,考虑MOA可以提高跨读评估的准确性,一致性和透明度.
结论:
- 通过整合机理学理解,包括MOA和代谢洞察力,基于SAR的横读得到了显著加强.
- 这种方法提高了对具有有限可用的数据的物质预测化学安全的可靠性.
- 考虑代谢激活途径和"活动悬崖"对于稳健的模拟选择和风险评估至关重要.
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