本项目研究的Keap1-Nrf2蛋白-蛋白相互作用是细胞炎性微环境调控的重要节点。抑制Keap1-Nrf2相互作用可以激活Keap1-Nrf2-ARE体系，促进谷胱甘肽合成、加速活性氧清除、增强异物代谢，最终改善细胞微环境，从根源上抑制炎性疾病的发生和发展。本研究着重针对已有Keap1-Nrf2抑制剂的化学结构的丰富性和多样性不足、对称性过高的问题，使用结合特征匹配碎片结构的方法进一步探索Keap1-Nrf2抑制剂的化学空间，发现结构新颖的Keap1-Nrf2抑制剂；同时针对小分子抑制剂-Keap1结合的动力学和热力学机制不明的问题，深入研究小分子-Keap1结合的分子作用机制，明确小分子-Keap1结合的动力学和热力学特征。通过上述研究，进一步阐明小分子调控Keap1-Nrf2蛋白-蛋白相互作用的作用机制，并为该靶标的创新药物开发提供化学结构多样的调控剂。

The Keap1-Nrf2 protein-protein interaction is the key node in the regulation of cellular inflammatory microenvironment. Effectively inhibiting the Keap1-Nrf2 protein-protein interaction can activate the Keap1-Nrf2-ARE system, thereby promote the synthesis of glutathione, accelerate the clearance of ROS and enhance the metabolism of extraneous matters, ultimately improving the cellular microenvironment and fundamentally inhibiting the occurrence and development of diseases. This project aims to solve the problems on the deficiency of the reported Keap1-Nrf2 small-molecule inhibitors including the insufficiency of the abundance and diversity of the chemical strucuture by matching binding determinants to the fragment structure, leading to the further investigation of the chemical spaces of the Keap1-Nrf2 inhibitors and the discovery of novel Keap1-Nrf2 inhibitors. On the other hand, this project also carries out the deep investigation on the molecule mechanism of the binding between small molecule inhibitors and Keap1 in order to validate the kinetic and dynamic characteristics of the binding. Based on the above research, this project expects to clarify the regulation mechanism of the Keap1-Nrf2 protein-protein interaction by small molecules and provide modulators with diverse chemical structures for the novel drug development of this target.