氨酰-tRNA合成酶是参与蛋白质合成和各种细胞生理反应的关键酶。除了它们标准的将氨基酸连接到相应的tRNA上的作用之外，它们还通过控制细胞内可溶性氨基酸的水平影响蛋白质稳态。例如，亮氨酰-tRNA合成酶（LARS1）充当哺乳动物雷帕霉素靶复合物1（mTORC1）的亮氨酸传感器，并可能作为mTORC1的异源激活因子RagD亚基的可能的GTP酶激活蛋白（GAP）。反过来，mTORC1调节细胞过程，如蛋白质合成、自噬和细胞生长，并涉及各种人类疾病，包括癌症、肥胖症、糖尿病和神经退行性疾病。因此，mTORC1抑制剂或破坏的mTORC1通路可提供潜在的癌症治疗方案。在本研究中，我们探究了阻止LARS感应和信号传递到mTORC1的结构要求。基于最近关于亮氨酸激活的mTORC1调节研究，我们奠定了针对mTORC1开发化学治疗剂的基础，这些化学治疗剂可克服对雷帕霉素的耐药性。使用组合的计算机模拟方法来开发和验证一种替代的互作模型，并讨论其优点和进展。最后，我们确定了一组化合物可供测试，以防止LARS1 / RagD蛋白质相互作用。我们为创建针对mTORC1的化学治疗药物奠定了基础，这可以征服对雷帕霉素的耐药性。我们利用计算机模拟方法生成和验证了一种替代的互作模型，概述了其优点和改进，并确定了一组新的物质可以防止LARS1 / RagD的相互作用。

Aminoacyl-tRNA synthetases are crucial enzymes involved in protein synthesis and various cellular physiological reactions. Aside from their standard role in linking amino acids to the corresponding tRNAs, they also impact protein homeostasis by controlling the level of soluble amino acids within the cell. For instance, leucyl-tRNA synthetase (LARS1) acts as a leucine sensor for the mammalian target of rapamycin complex 1 (mTORC1), and may also function as a probable GTPase-activating protein (GAP) for the RagD subunit of the heteromeric activator of mTORC1. In turn, mTORC1 regulates cellular processes, such as protein synthesis, autophagy, and cell growth, and is implicated in various human diseases including cancer, obesity, diabetes, and neurodegeneration. Hence, inhibitors of mTORC1 or a deregulated mTORC1 pathway may offer potential cancer therapies. In this study, we investigated the structural requirements for preventing the sensing and signal transmission from LARS to mTORC1. Building upon recent studies on mTORC1 regulation activation by leucine, we lay the foundation for the development of chemotherapeutic agents against mTORC1 that can overcome resistance to rapamycin. Using a combination of in-silico approaches to develop and validate an alternative interaction model, discussing its benefits and advancements. Finally, we identified a set of compounds ready for testing to prevent LARS1/RagD protein-protein interactions. We establish a basis for creating chemotherapeutic drugs targeting mTORC1, which can conquer resistance to rapamycin. We utilize in-silico methods to generate and confirm an alternative interaction model, outlining its advantages and improvements, and pinpoint a group of novel substances that can prevent LARS1/RagD interactions.Communicated by Ramaswamy H. Sarma.