蛋白-蛋白相互作用抑制剂的成药性是限制其研究和开发的关键问题。本项目的核心是探索蛋白-蛋白相互作用抑制剂设计中分子活性和成药性的协同设计和优化方法。主要的研究思路是基于蛋白-蛋白相互作用的物理化学行为合理设计活性和成药性兼顾的抑制剂。即通过合理整合药物-蛋白的微观相互作用、药物-蛋白结合的宏观物理化学性质和药物分子自身的理化性质于蛋白-蛋白相互作用抑制剂的设计和优化之中，从药物分子设计的源头优化蛋白-蛋白相互作用抑制剂的成药性。本项目以Keap1-Nrf2蛋白-蛋白相互作用抑制剂为对象，通过系统研究抑制剂和靶标结合的结合热力学和结合动力学性质，总结结合过程的物理化学规律。以此为基础，通过熵-焓转换机制，结合抑制剂的理化性质参数、透膜性和细胞活性，多维度协同优化Keap1-Nrf2蛋白-蛋白相互作用抑制剂的活性和成药性，以更好探索Keap1-Nrf2抑制剂的治疗学应用。

Drug-like properties are the key issues for developing protein-protein interaction inhibitors. In this project, we aim to develop novel drug design methods that can balance the biological activities and drug-like properties. The binding physical chemistry process between the inhibitor and the protein target is chosen as a breakthrough. Based on the binding physical chemistry disciplines, microscopic intermolecular interactions, macroscopic physical chemistry effects and detailed molecular properties can be coordinated to optimize the protein-protein interaction inhibitors. It can improve the drug-like properties in the first place. We chose Keap1-Nrf2 protein-protein interaction as the object, and systemically investigated the binding kinetics and binding thermodynamics of this target. After that, by incorporating the enthalpy–entropy compensation theory, the inhibitors will be designed to collaborative optimize the molecular physicochemical properties, cell membrane permeability and cellular activities. The resulting inhibitors not only can further validate this target, but also can benfit the drug development process.