Molecular docking and interaction profiling identify phytochemicals as candidate JAK-STAT pathway inhibitors in rheumatoid arthritis

Rheumatoid arthritis (RA) remains a challenging chronic disease as despite adherence to known therapeutic guidelines nearly half of patients experience persistent moderate to severe disease activity. Pathogenesis is driven by multiple pro-inflammatory signalling pathways that includes Janus kinase/signal transducer and activator of transcription (JAK/STAT), NF-κB, Notch and MAPK, thereby driving macrophage polarization toward the pathogenic M1 phenotype. JAKis modulate different cytokine pathways at once causing both benefits and risks, such as improved outcomes in hyperinflammatory conditions and increased susceptibility to certain infections. However standard JAKis’s show adverse side effects motivating the search for safer alternatives. In this study in-silico molecular docking, ligand efficiency and selectivity index (SI) analyses was performed for 10 ligands to identify phytochemicals with high binding affinity to JAK family proteins, to recommend potential safer plant derived alternative inhibitors for RA therapy. Quercetin showed the strongest affinity toward JAK2 (− 9.3 kcal/mol), comparable to the reference drug baricitinib (− 8.2 kcal/mol), and peficitinib against JAK1 and JAK3 (− 9.0 kcal/mol). Similarly, kaempferol and catechin exhibited strong binding to JAK2 (− 8.9 kcal/mol, − 8.8 kcal/mol, respectively) and JAK3 (− 8.5 kcal/mol, − 8.8 kcal/mol, respectively), indicating their potential as pan-JAK inhibitors. SI analysis indicated marginally favourable target-engagement profiles for quercetin (SI = 1.18), naringenin (SI = 1.15), and kaempferol (SI = 1.14) relative to standard JAK inhibitors. In spite of lower SI (1.08), catechin has high absolute binding affinities for all four JAK isoforms, which supports its candidature as pan-JAK modulator. Together, these four phytochemicals warrant further preclinical evaluation as candidate modulators of the JAK/STAT pathway in RA, potentially expanding the therapeutic options available for managing this disease.