Discovery of 5-(1-benzyl-1H-imidazol-4-yl)-1,2,4-oxadiazole derivatives as novel RIPK1 inhibitors via structure-based virtual screening

  • Drug Dev Res. 2024 Aug;85(5):e22235. doi: 10.1002/ddr.22235.
Yanzhen Yu  1 ,  Yunzhen Hu  2 ,  Huihui Yan  1 ,  Xin Zeng  1 ,  Haodong Yang  3 ,  Lei Xu  4 ,  Rong Sheng  1  3
Affiliations
  • 1. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
  • 2. Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 3. Jinhua Institute of Zhejiang University, Zhejiang University, Jinhua, China.
  • 4. Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, China.
PMID: 39021343 DOI: 10.1002/ddr.22235
Abstract

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 IC50 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.

Keywords
RIPK1 inhibitors; molecular dynamics; virtual screening.
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