蛋白质介导分子引发器官特异性毒性事件的结构-活性关系
Nisreen H K Isbaita1, Stefania Gardoni1, Alessandra Roncaglioni1
1Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Environmental Health Sciences, via Mario Negri 2, 20158 Milan, Italy.
Chemical research in toxicology
|December 24, 2025
概括
这项研究开发了结构-活性关系,使用结构警报来预测化学毒性,与3Rs原则保持一致. 新模型显示了高通量查的强大预测性能,减少了动物试验.
科学领域:
- 毒理学 毒理学 毒理学
- 计算化学计算化学
- 药理学 药理学是指药理学的学科.
背景情况:
- 毒理学研究正在从动物模型过渡到体外和in silico方法.
- 这一转变旨在提高成本效益,加快化学选,并坚持3Rs原则 (取代,减少,改进) 以尽量减少动物的痛苦.
研究的目的:
- 根据结构性警报 (SAs) 开发结构-活动关系 (SARs).
- 预测与特定毒性相关的化学诱导分子启动事件 (MIE).
- 创建用于高通量和初步化学安全测试的预测模型.
主要方法:
- 从不良结果途径网络中确定了29个蛋白质标.
- 从ChEMBL 35数据库收集化学生物活性数据.
- 在DeltaQSAR软件中利用SARpy 2.0提取蛋白质生物活性的SAR规则集 (SAS集合).
主要成果:
- 制定了29个目标的规则,将结构性警报与蛋白质生物活性联系起来.
- 使用外部测试集对现实生活中的预测性进行评估的规则集.
- 在29个规则集中,22个规则集取得了良好的外部验证性能 (平衡精度≥70%,覆盖率≥70%).
结论:
- 开发的规则集显示了对化学毒性的高预测能力.
- 这些SAR模型可以有效地用于高通量和初步化学安全评估.
- 将SAR与不良结果途径相结合,为毒理学预测提供了机制基础.
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