慢性肾病（CKD）发病机制复杂，涉及与炎症、纤维化等相关的多条下游信号通路的异常，治疗困难、危害性大。现有药物多只针对个别通路，无法同时阻断所有通路，各通路间的交叉对话导致其疗效不佳。因此，CKD治疗药物研究尚无实质性进展。近年来，同源结构域相互作用蛋白激酶-2（HIPK2）作为药物潜在靶标备受关注。HIPK2可同时调节下游各通路，在CKD发生发展中起重要作用，选择性HIPK2抑制剂有望克服上述缺陷，但目前尚未发现系统的HIPK2抑制剂构效关系研究的有关报道。我们前期研究发现化合物WGY215和WZY306能在选择性抑制HIPK2的同时发挥较强的抗肾纤维化活性和低肾毒性。本项目将在此基础上，借助计算机辅助药物设计等策略，开展蛋白同源模建、虚拟筛选、构效关系和作用机制研究。本研究有望在HIPK2的靶标确认以及选择性抑制剂研究方面取得突破性进展，为CKD的药物治疗提供新思路和候选分子。

Chronic kidney disease (CKD) is characterized by its high risk and complex pathogenesis, involving multiple downstream signaling pathways associated with inflammation and fibrosis. Most of existing drugs target individual pathways and can not block all the downstream pathways at the same time. The crosstalk between the various pathways leads to poor efficacy of these drugs. Therefore, there is no substantial progress in the research of CKD drug discovery. In recent years, homeodomain interacting protein kinase -2 (HIPK2) has attracted much attention as a potential drug target. HIPK2 can regulate the downstream pathways at the same time, which plays an important role in the occurrence and development of CKD. Therefore, selective HIPK2 inhibitors are expected to overcome the defects mentioned above. However, there is no systematic report on the structure-activity relationship of HIPK2 inhibitors up to now. In our previous study, we found that compounds WGY215 and WZY306 can inhibit the activity of HIPK2 selectively and inhibit renal fibrosis with low toxicity. In this study, based on our previous achievements, protein homology modeling, virtual screening, structure-activity relationship and mechanism of action studies will be conducted with the aid of computer-aided drug design and other methods. It is expected to make a breakthrough in the study of target validation and selective inhibitor discovery of HIPK2, and will also provide new ideas and candidate molecules for CKD drug therapy.