• IMMUNE NETWORK
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• 제13권6호
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• pp.283-288
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• 2013

The pro-inflammatory cytokines tumor necrosis factor-${\alpha}$ (TNF${\alpha}$) and interleukin (IL)-$1{\beta}$ are crucial mediators involved in chronic inflammatory diseases. Inflammatory signal pathways regulate inflammatory cytokine expression-mediated by p38 mitogen activated protein kinase (p38MAPK). Therefore, considerable attention has been given to p38MAPK as a target molecule for the development of a novel anti-inflammatory therapeutics. BIRB 796, one of p38MAPK inhibitor, is a candidate of therapeutic drug for chronic inflammatory diseases. In this study, we investigated the effect of BIRB 796 on inflammatory cytokine productions by lipopolysaccharide (LPS) in different immune cell types. BIRB 796 reduced LPS-mediated IL-8 production in THP-1 cells but not in Raw 264.7 cells. Further analysis of signal molecules by western blot revealed that BIRB 796 sufficiently suppressed LPS-mediated phosphorylation of p38MAPK in both cell types whereas it failed to block inhibitor of kappa B (I-${\kappa}B$) degradation in Raw 264.7 cells. Taken together, these results suggest that the anti-inflammatory function of BIRB 796 depends on cell types.

• Bulletin of the Korean Chemical Society
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• 제35권8호
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• pp.2494-2504
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• 2014

P38 mitogen activated protein (MAP) kinase is an important anti-inflammatory drug target, which can be activated by responding to various stimuli such as stress and immune response. Based on the conformation of the conserved DFG loop (in or out), binding inhibitors are termed as type-I and II. Type-I inhibitors are ATP competitive, whereas type-II inhibitors bind in DFG-out conformation of allosteric pocket. It remains unclear that how these allosteric inhibitors stabilize the DFG-out conformation and interact. Organosilicon compounds provide unusual opportunity to enhance potency and diversity of drug molecules due to their low toxicity. However, very few examples have been reported to utilize this property. In this regard, we performed docking of an inhibitor (BIRB) and its silicon analog (Si-BIRB) in an allosteric binding pocket of p38. Further, molecular dynamics (MD) simulations were performed to study the dynamic behavior of the simulated complexes. The difference in the biological activity and mechanism of action of the simulated inhibitors could be explained based on the molecular mechanics/generalized Born surface area (MM/GBSA) binding free energy per residue decomposition. MM/GBSA showed that biological activities were related with calculated binding free energy of inhibitors. Analyses of the per-residue decomposed energy indicated that van der Waals and non-polar interactions were predominant in the ligand-protein interactions. Further, crucial residues identified for hydrogen bond, salt bridge and hydrophobic interactions were Tyr35, Lys53, Glu71, Leu74, Leu75, Ile84, Met109, Leu167, Asp168 and Phe169. Our results indicate that stronger hydrophobic interaction of Si-BIRB with the binding site residues could be responsible for its greater binding affinity compared with BIRB.