Molecular Docking and Pharmacokinetic Evaluation of Newly Synthesized Prodrug ‘Tofamesa’ as an Inhibitor of JAK3 in Inflammatory Bowel Disease

Abstract

This investigation is an important target in the Janus Kinase Signal Transducer and activator of transcription(JAK-STAT) signalling pathway for the treatment of autoimmune and inflammatory disorders like ulcerative colitis. The present work describes our molecular docking interactions with a new prodrug called ‘Tofamesa’, formed by a combination of Tofacitinib, Mesalamine, and PEG400, against JAK3 (PDB ID: modified P52333). The Swiss Dock simulations were carried out with docking parameters (box centre: 4, -10, -6; box size: 20 × 20 × 20), which indicated moderate binding affinities in the range of -4.820 to -3.173 kcal/mol. Compared with known JAK3 inhibitors such as Tofacitinib (-7 to -10 kcal/mol), we observe weaker binding of Tofamesa, suggesting that modifications to its structure may increase its inhibitory activity. Swiss ADME predictions provide insight with favourable predictions of physicochemical properties, including solubility, moderately lipophilic (Log Po/w: 3.08), and minimal CYP-mediated drug interactions, which would reduce the likelihood of pharmacokinetic complications. However, combined with low gastrointestinal absorption, high efflux by P-glycoprotein (P-gp) transporters will restrain oral bioavailability. Limited transfer across the blood-brain barrier (BBB) provides safety from CNS-side effects; nevertheless, targeted delivery through lipid-based carrier systems may require optimization for systemic availability. Inclusion Conclusion Tofamesa demonstrates favourable solubility and safety features, but further optimization is warranted to increase its potency as a JAK3 inhibitor and oral bioavailability. Future studies will target structural refinement and enhancement of the formulation to improve its therapeutic efficacy in inflammatory bowel disease.