Virtual Screening-based Molecular Analysis of Marine Bioactive Molecules as Inhibitors for Janus Kinase 3

Abstract

Rheumatoid arthritis (RA), a chronic autoimmune disorder, can cause joint deformity and disability. The Janus kinases (JAKs), intracellular tyrosine kinases family (includes JAK1, JAK2, and JAK3), play an essential role in the signaling of various cytokines and are implicated in the pathogenesis of inflammatory diseases, including RA. Consequently, JAKs have attracted significant attention in recent years as therapeutic targets of RA. In the current study, we explored the role of a set of biomolecules from marine sources that could be used as specific inhibitors of JAKs and treat arthritis. The binding affinity of these molecules including astaxanthin (ATX), fucoxanthin (FX), fuscoside E (FsE), fucosterol (Fs), and phlorofucofuroeckol (PFFE) JAK3 has been analyzed. In addition, the details of relative structural interactions have been compared to those of the recently Food and Drug Administration-approved inhibitor, tofacitinib. Interestingly, some of these marine biomolecules showed a higher binding energy (b.e.) and specific binding to JAK3 active/potential sites when compared to the approved inhibitors. For instance, FsE binds to two key regulator residues of JAK3 required for its activity and for inhibitor stability, CYS909 and LYS905, with higher b.e. (-9.6) than the approved inhibitors. Thus, FsE may have a potential inhibitory action on JAKs and especially on JAK3. Additionally, PFFE can bind to several kinase critical regulators of JAK3 and the b.e. may reach -10.7. Based on the evaluation of oral availability, drug-likeness, pharmacokinetics, and medicinal chemistry friendliness, FsE seems to be the most appropriate potential inhibitor for JAK3.