Discovery of novel inhibitors targeting the macrophage migration inhibitory factor via structure-based virtual screening and bioassays.
Macrophage migration inhibitory factor (MIF) is involved in regulation of both the innate and the adaptive immune responses and is regarded as an attractive anti-inflammatory pharmacological target. In this study, molecular docking-based virtual screening and in vitro bioassays were utilized to identify novel small-molecule inhibitors of MIF. The in vitro enzyme-based assay identified that ten chemically diverse compounds exhibited potent inhibitory activity against MIF in the micromolar regime, including three compounds with IC50 values below 10 μM and one with an IC50 value below 1 μM (0.55 μM); the latter is 26-fold more potent than the reference compound ISO-1. The structural analysis demonstrates that most of these active compounds possess novel structural scaffolds. Further in vitro cell-based glucocorticoid overriding, chemotaxis, and Western blotting assays revealed that the three compounds can effectively inhibit the biological functions of MIF in vitro, suggesting that these compounds could be potential agents for treating inflammatory diseases.
College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang 310058, People's Republic of China.
Lei
L
Xu
Yu
Y
Zhang
Longtai
L
Zheng
Chunhua
C
Qiao
Youyong
Y
Li
Dan
D
Li
Xuechu
X
Zhen
Tingjun
T
Hou
D000818:Animals; D001681:Biological Assay; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D020128:Inhibitory Concentration 50; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure
D004791:Enzyme Inhibitors; D008263:Macrophage Migration-Inhibitory Factors