Towards an molecular initiating event Atlas: more chemistry-less testing

• 作 者: Johnathon Goodman
• 机 构: Department of Chemistry, The University of Cambridge, UK
• 出 处: 2016(第二届)毒性测试替代方法与转化毒理学(国际)学术研讨会暨有害结局路径(AOP)与风险评估培训会议
• 发表日期: 2016年12期

　　How can we use our knowledge of chemistry to help us understand issues in toxicology? We can calculate structure, reactivity and physical properties, for many molecules,with a high degree of precision and at tractable computational cost.Using this knowledge, we consider how a molecule will first interact with a biological system, the Molecular Initiating Event (MIE), in a way that starts an Adverse Outcome Pathway (AOP).As we build our understanding of MIEs, we begin to move towards our ultimate goal of predicting all toxicological effects from the two dimensional structure of a molecule.The AOP approach describes how molecules lead to adverse outcomes.Every AOP begins with an MIE, and this is the key event for which chemical knowledge can be central to the analysis and mapping.For example, skin sensitization can be understood within this framework: a complex cascade of biological processes starts with the interaction between a molecule and biomolecule.Without this key molecular initiating event, the process of skin sensitization cannot happen.We can investigate MIEs for other molecules, in cases where the molecule has been studied in detail.This is not an obvious reduction in complexity, because there are more MIEs than molecules.However, even with the few molecules studied so far, the number of MIEs increases less quickly than the number of molecules, and so a sufficiently large group of molecules will lead to simplification.As the number of molecules we analyse grows, we are beginning to build up a map of the available MIEs.This is only possible because we are able to calculate molecular structures, properties and reactivity with reasonable precision and accessible speed.Chemical information from diverse sources can be ordered and analysed automatically in order to develop the more comprehensive picture of chemistry that is required to build a molecule-based approach to toxicology.