Flavipin from fungi as a potential inhibitor of rheumatoid arthritis signaling molecules

AbstractFlavipin, a fungal lower molecular weight biomolecule (MW 196.16 g/mol), has not been yet extensively studied for beneficial preclinical and clinical applications. In recent years, various preclinical mouse models including adjuvant-induced arthritis (AIA) were employed to understand mechanisms associated with Rheumatoid arthritis (RA) and to develop new therapeutic drugs. In the current study, we studied the inhibitory effect of Flavipin on major signaling molecules involved in the inflammatory response during RA using both in-silico virtual interaction and in vivo mouse model of AIA. Ourin-silico results clarified that Flavipin interacts with the tumor necrosis factor alpha (TNF- α) through conventional hydrogen binding (H–H) at one of TNF-α critical amino acids tyrosine residues, Tyr119, with binding energy (b.e.) −5.9. In addition, Flavipin binds to ATP-binging sites of the Jesus kinases, JAK1, JAK2 and JAK3, through H–H (b. e. between −5.8 and −6.1) and then i t may inhibit JAKs, regulators of RA signaling molecules. Moreover, our molecular dynamics stimulation for the docked TNF-α/Flavipin complex confirmed the specificity and the stability of the interaction. In vitro, Flavipin is not toxic to normal cells at doses below 50 µM (its IC50 in normal fib roblast cell line was above 100 µM). However, in vivo, the arthritis score and hind paw oedema parameters were modulated in Flavipin treated mice. Consistent with the in-silico results the levels o...
Source: Inflammopharmacology - Category: Drugs & Pharmacology Source Type: research