Yu Yanzhen, Hu Yunzhen, Yan Huihui, Zeng Xin, Yang Haodong, Xu Lei, Sheng Rong
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Drug Dev Res. 2024 Aug;85(5):e22235. doi: 10.1002/ddr.22235.
RIPK1 plays a key role in necroptosis and is associated with various inflammatory diseases. Using structure-based virtual screening, a novel hit with 5-(1-benzyl-1H-imidazol-4-yl)-1,2,4-oxadiazole scaffold was identified as an RIPK1 inhibitor with an IC value of 1.3 μM. Further structure-activity relationship study was performed based on similarity research and biological evaluation. The molecular dynamics simulation of compound 2 with RIPK1 indicated that it may act as a type II kinase inhibitor. This study provides a highly efficient way to discover novel scaffold RIPK1 inhibitors for further development.
RIPK1在坏死性凋亡中起关键作用，并与多种炎症性疾病相关。通过基于结构的虚拟筛选，一种具有5-(1-苄基-1H-咪唑-4-基)-1,2,4-恶二唑骨架的新型命中化合物被鉴定为RIPK1抑制剂，其IC值为1.3 μM。基于相似性研究和生物学评价进行了进一步的构效关系研究。化合物2与RIPK1的分子动力学模拟表明它可能作为一种II型激酶抑制剂。本研究为发现新型骨架RIPK1抑制剂以供进一步开发提供了一种高效方法。
