Identification of a novel and high affinity MIF inhibitor via structure-based pharmacophore modelling, molecular docking, molecular dynamics simulations, and biological evaluation

Macrophage migration inhibitory factor (MIF) plays a crucial role in disrupting immune homeostasis and was overexpressed in immune cells. The inhibitors of MIF inhibit the release of inflammatory factors to treat sepsis. Herein, a series of compounds (termed as Hits 1-6) were discovered based on pharmacophore modelling, molecular docking, and interaction analysis. The biaryltriazole inhibitor 3a was used as the positive control. MST and ITC experiments showed that compared to 3a, Hit-1 possessed the highest affinity with MIF. MD simulations exhibited that Hit-1 stably bound to the active pocket of MIF. Pull down experiment showed that Hit-1 could interfere with the binding of MIF to CD74. Furthermore, RT-qPCR demonstrated that Hit-1 suppressed the release of pro-inflammatory cytokines in macrophages including TNF-α, IL-6, and IL-1β. These data demonstrate that Hit-1 may be a promising and high-affinity candidate compound treating sepsis.

MD simulations; MIF; biological evaluation; molecular docking; structure-based pharmacophore modelling.