Sahoo Ajaya Kumar, Baskaran Shanmuga Priya, Chivukula Nikhil, Kumar Kishan, Samal Areejit
The Institute of Mathematical Sciences (IMSc) Chennai 600113 India
Homi Bhabha National Institute (HBNI) Mumbai 400094 India.
RSC Adv. 2023 Aug 4;13(34):23461-23471. doi: 10.1039/d3ra04452a.
The thyroid stimulating hormone receptor (TSHR) is crucial in thyroid hormone production in humans, and dysregulation in TSHR activation can lead to adverse health effects such as hypothyroidism and Graves' disease. Further, animal studies have shown that binding of endocrine disrupting chemicals (EDCs) with TSHR can lead to developmental toxicity. Hence, several such chemicals have been screened for their adverse physiological effects in human cell lines high-throughput assays in the ToxCast project. The invaluable data generated by the ToxCast project has enabled the development of toxicity predictors, but they can be limited in their predictive ability due to the heterogeneity in structure-activity relationships among chemicals. Here, we systematically investigated the heterogeneity in structure-activity as well as structure-mechanism relationships among the TSHR binding chemicals from ToxCast. By employing a structure-activity similarity (SAS) map, we identified 79 activity cliffs among 509 chemicals in TSHR agonist dataset and 69 activity cliffs among 650 chemicals in the TSHR antagonist dataset. Further, by using the matched molecular pair (MMP) approach, we find that the resultant activity cliffs (MMP-cliffs) are a subset of activity cliffs identified the SAS map approach. Subsequently, by leveraging ToxCast mechanism of action (MOA) annotations for chemicals common to both TSHR agonist and TSHR antagonist datasets, we identified 3 chemical pairs as strong MOA-cliffs and 19 chemical pairs as weak MOA-cliffs. In conclusion, the insights from this systematic investigation of the TSHR binding chemicals are likely to inform ongoing efforts towards development of better predictive toxicity models for characterization of the chemical exposome.
促甲状腺激素受体（TSHR）在人类甲状腺激素生成过程中至关重要，TSHR激活失调会导致如甲状腺功能减退和格雷夫斯病等不良健康影响。此外，动物研究表明，内分泌干扰化学物质（EDCs）与TSHR结合会导致发育毒性。因此，在ToxCast项目中，已经通过高通量检测在人类细胞系中筛选了几种此类化学物质的不良生理效应。ToxCast项目产生的宝贵数据推动了毒性预测模型的开发，但由于化学物质之间结构 - 活性关系的异质性，这些模型的预测能力可能受到限制。在此，我们系统地研究了ToxCast中TSHR结合化学物质之间结构 - 活性以及结构 - 作用机制关系的异质性。通过使用结构 - 活性相似性（SAS）图，我们在TSHR激动剂数据集中的509种化学物质中识别出79个活性悬崖，在TSHR拮抗剂数据集中的650种化学物质中识别出69个活性悬崖。此外，通过使用匹配分子对（MMP）方法，我们发现所得的活性悬崖（MMP - 悬崖）是通过SAS图方法识别出的活性悬崖的一个子集。随后，通过利用TSHR激动剂和TSHR拮抗剂数据集共有的化学物质的ToxCast作用机制（MOA）注释，我们识别出3对化学物质为强MOA - 悬崖，19对化学物质为弱MOA - 悬崖。总之，对TSHR结合化学物质的这一系统研究所得出的见解可能会为正在进行的开发更好的预测毒性模型以表征化学暴露组的努力提供信息。
