Article

Discovery of novel MIF inhibitors that attenuate microglial inflammatory activation by structures-based virtual screening and in vitro bioassays

Yu Zhang1, Lei Xu2, Yao Zhang1, Jie Pan1, Pu-qing Wang1, Sheng Tian3, Huan-ting Li4, Bo-wen Gao4, Ting-jun Hou5, Xue-chu Zhen3, Long-Tai Zheng3
1 Department of Pharmacy, Hubei Clinical Research Center of Parkinson’s disease, Xiangyang Key Laboratory of Movement Disorders, Xiangyang No.1 People’Hospital, Hubei University of Medicine, Xiangyang 441000, China
2 Institute of Bioinformatics and Medical Engineering, Jiangsu University of Technology, Changzhou 213001, China
3 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
4 School of Pharmacy, Baotou Medical College, Baotou 014060, China
5 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
Correspondence to: Ting-jun Hou: tjhou@zju.edu.cn, Xue-chu Zhen: zhenxuechu@suda.edun.cn, Long-Tai Zheng: zhenglongtai@suda.edu.cn,
DOI: 10.1038/s41401-021-00753-x
Received: 12 April 2021
Accepted: 27 July 2021
Advance online: 24 August 2021

Abstract

Macrophage migration inhibitory factor (MIF) is a pluripotent pro-inflammatory cytokine and is related to acute and chronic inflammatory responses, immune disorders, tumors, and other diseases. In this study, an integrated virtual screening strategy and bioassays were used to search for potent MIF inhibitors. Twelve compounds with better bioactivity than the prototypical MIF-inhibitor ISO-1 (IC50 = 14.41 μM) were identified by an in vitro enzymatic activity assay. Structural analysis revealed that these inhibitors have novel structural scaffolds. Compound 11 was then chosen for further characterization in vitro, and it exhibited marked anti-inflammatory efficacy in LPS-activated BV-2 microglial cells by suppressing the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs). Our findings suggest that MIF may be involved in the regulation of microglial inflammatory activation and that small-molecule MIF inhibitors may serve as promising therapeutic agents for neuroinflammatory diseases.
Keywords: macrophage migration inhibitory factor; virtual screening; tautomerase assay; naive Bayesian classification; neuroinflammation

Article Options

Download Citation

Cited times in Scopus

Share