Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that is mediated by pro-inflammatory cytokines, like interleukin-6 (IL-6). IL-6 plays an important role in synovial inflammation and joint degradation. In this study, a combined in silico, in vitro and in vivo approach was used to identify and preliminarily evaluate valganciclovir hydrochloride as potential modulator of IL-6 receptor mediated inflammatory signalling. Docking studies showed that valganciclovir hydrochloride had favourable binding affinity with IL-6 receptor, and interacted stably with active site. ADMET analysis showed that compound possessed desirable ADMET properties, with good absorption and distribution, and low toxicity. Molecular binding free energy indicated stability of the protein-ligand complex. Moreover, 100 ns molecular dynamics simulation showed stable RMSD, with consistent key interactions, suggesting a dynamically stable protein-ligand complex in the physiological environment. Binding assay further demonstrated concentration dependent inhibition of IL-6:IL-6R interaction. Furthermore, in vivo assessment in collagen induced arthritis rats showed that treatment with valganciclovir hydrochloride resulted in marked reduction in disease severity. The treatment groups demonstrated a decrease in paw swelling, ESR, CRP, RF and IL-6 expression. Treatment also reduced downstream inflammatory mediators such as IL-17, MMP-9, p-STAT3, STAT3 and JAK2, suggesting attenuation of IL-6 associated inflammatory signalling In addition, antioxidant enzyme levels were restored with reduction in lipid peroxidation. The results indicate that valganciclovir hydrochloride has favourable binding interactions, and pharmacokinetics, as well as strong anti-inflammatory and anti-arthritic potential. The combined computational and experimental results support the possible involvement of IL-6/JAK2/STAT3 associated signalling pathways in observed anti-arthritic effects of valganciclovir hydrochloride.