IL-6 is a pro-inflammatory cytokine which mediates inflammation and immune response. It participates in multiple biological activities by binding to membrane receptor GP130 and triggering Jak/STAT3 trans-signaling pathway. Excessive induction of this pathway has been observed in various diseases like neuro-inflammation and cancers. Blockade of IL-6/GP130 signaling became a novel therapeutic approach. However, few small molecule inhibitors have been reported so far. More importantly, a structure-based rationale for IL-6/GP130 inhibitor design was absent. This poster will present how we utilized computational methods to develop effective IL-6/GP130 inhibitors. Through computational analyses on IL-6/IL-Rα/GP130 complex, we identified two hot spots on GP130 D1 domain which contribute most to the hexamerization protein-protein interaction. Then a series of small molecules were designed accordingly to disrupt these key “hot spots”. Inhibitors showed successful blockade on IL6 trans-signaling in cancer cellular assays. In order to improve binding affinity, under the guidance of molecular dockings and dynamic simulations, we further explored the GP130 D1 domain interaction surface and re-arranged the inhibitors into new scaffolds capable of capturing more interactions on GP130. Computational free energy analyses were also performed to compare with direct molecular binding energy results to guide our iterative design and mechanistic understanding.<br/><b>Acknowledgement.</b> We thank NIH R01 NS088437 for partial financial support for this project.

Structure-based computer-aided IL-6/GP130 protein-protein interaction (PPI) inhibitor design

251st National Meeting (2016)

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