Perspective for Discovery of Small Molecule IL-6 Inhibitors through Study of Structure–Activity Relationships and Molecular Docking

Abstract

) is a proinflammatory cytokine that plays a key role in the pathogenesis and physiology of inflammatory and autoimmune diseases, such as coronary heart disease, cancer, Alzheimer's disease, asthma, rheumatoid arthritis, and most recently COVID-19. IL-6 and its signaling pathway are promising targets in the treatment of inflammatory and autoimmune diseases. Although, anti-IL-6 monoclonal antibodies are currently being used in clinics, huge unmet medical needs remain because of the high cost, administration-related toxicity, lack of opportunity for oral dosing, and potential immunogenicity of monoclonal antibody therapy. Furthermore, nonresponse or loss of response to monoclonal antibody therapy has been reported, which increases the importance of optimizing drug therapy with small molecule drugs. This work aims to provide a perspective for the discovery of novel small molecule IL-6 inhibitors by the analysis of the structure−activity relationships and computational studies for protein−protein inhibitors targeting the IL-6/IL-6 receptor/gp130 complex.

Anti-Inflammatory Sesquiterpenes from Fruiting Bodies of Schizophyllum commune

“…Inflammation is the basic defense mechanism of immunization and can protect against injuries caused by harmful stimuli. , Several cell types such as macrophages and T cells together with extracellular mediators of the immune system are keys for the regulation of the inflammatory process . As pro-inflammatory cytokines, IL-6 and IL-1β are produced by multifarious cells and play an important role in the regulation of inflammation, immune responses, and the acute-phase reaction. , Particularly, IL-6 was deemed as the key mediator of chronic disease pathogenesis in a wide range of pathological inflammatory situations, including end-stage renal disease and rheumatoid arthritis . Therefore, compounds which can regulate production of IL-1β and IL-6 in LPS-stimulated macrophages have the potential to be developed into novel anti-inflammatory drugs.…”

Integration of Hybridization Strategies in Pyridine–Urea Scaffolds for Novel Anticancer Agents: Design, Synthesis, and Mechanistic Insights

“…One such application involves predicting the binding modes between a ligand and its target, enabling the ranking of compounds based on their docking scores and establishing a relationship between these scores and potential activity [ 32 ]. The visualization of interactions obtained from docking studies can further assist in improving the affinity characteristics of the ligands under investigation [ 33 ]. Consequently, a thorough molecular docking analysis was conducted to assess the binding affinity of the best cytotoxic compounds, compounds 8a , 8h , and 8i , towards VEGFR2.…”

N,N‐Diarylsulfonamide Reduces Proinflammatory Cytokine Interleukin‐6 Levels in Cells through Nuclear Factor‐κB Regulation

“…[10] The docking study indicated that MDL-A interacts with gp130 and thereby interferes in IL-6 binding to gp130 resulting in inhibition of IL-6 signaling. [11] The Brassica bioactive compounds were found to have antiinflammatory activity and showed a reduction in IL-6 levels. [12] JAK kinase which is part of the IL-6 signaling pathway has been targeted for the development of inhibitors in recent times.…”