Abstract
HMGB1 is a key molecule that both triggers and sustains inflammation following infection or injury, and is involved in a large number of pathologies, including cancer. HMGB1 participates in the recruitment of inflammatory cells, forming a heterocomplex with the chemokine CXCL12 (HMGB1·CXCL12), thereby activating the G-protein coupled receptor CXCR4. Thus, identification of molecules that disrupt this heterocomplex can offer novel pharmacological opportunities to treat inflammation-related diseases. To identify new HMGB1·CXCL12 inhibitors we have performed a study on the ligandability of the single HMG boxes of HMGB1 followed by a virtual screening campaign on both HMG boxes using Zbc Drugs and three different docking programs (Glide, AutoDock Vina, and AutoDock 4.2.6). The best poses in terms of scoring functions, visual inspection, and predicted ADME properties were further filtered according to a pharmacophore model based on known HMGB1 binders and clustered according to their structures. Eight compounds representative of the clusters were tested for HMGB1 binding by NMR. We identified 5,5′-methylenedi-2,3-cresotic acid (2a) as a binder of both HMGB1 and CXCL12; 2a also targets the HMGB1·CXCL12 heterocomplex. In cell migration assays 2a inhibited the chemotactic activity of HMGB1·CXCL12 with IC50 in the subnanomolar range, the best documented up to now. These results pave the way for future structure activity relationship studies to optimize the pharmacological targeting of HMGB1·CXCL12 for anti-inflammatory purposes.
Highlights
Cell recruitment is a fundamental event in the establishment of both acute and chronic inflammatory responses (Charo and Ransohoff, 2006)
We first searched for potential druggable hot spots on High Mobility Group Box 1 (HMGB1) surfaces using the computational solvent mapping programs FTMap (Kozakov et al, 2015) and Dogsite (Volkamer et al, 2012)
CS2 CS3, CS5, and CS7 were within a distance of 8 Å, defining the highest density hot spot (39 probes), located at the interface of the two helices forming the short arm of the L-shaped fold (Figure 1A)
Summary
Cell recruitment is a fundamental event in the establishment of both acute and chronic inflammatory responses (Charo and Ransohoff, 2006) Chemokines and their receptors organize leukocyte trafficking and migration to the tissues both in healthy and pathological conditions (Griffith et al, 2014). The cytokine-like function of HMGB1 upon inflammatory stimuli after infection or injury relies on the interaction of its reduced form with CXCL12, which promotes CXCR4-dependent recruitment of inflammatory cells to injured tissues (Schiraldi et al, 2012) and exacerbates the immune response in pathological conditions (Proudfoot and Uguccioni, 2016; D’Agostino et al, 2018). The disruption of the HMGB1·CXCL12 heterocomplex with small molecules might offer new and selective strategies against inflammation related diseases (Venereau et al, 2016; VanPatten and Al-Abed, 2018)
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