Comprehensive Computational Strategies for Multi -Target Drug Discovery in Inflammatory Bowel Disease Utilizing Bioactive Compounds

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease that includes ulcerative colitis and Crohn's disease. Based on the pathogenesis of the disease, simultaneously targeting inflammation and the epithelial barrier could have an effective role in improving the symptoms of this disease. Previously, each of these therapeutic targets, PDE۴, PHD۱, and PHD۲, has been investigated separately. But finding small molecules that can inhibit multi-targets is so essential for treating diseases with multi-pathways like IBD. The enzyme phosphodiesterase ۴ (PDE۴) plays an important role in inflammation. PDE۴ is involved in the production of inflammatory cytokines by converting cAMP to AMP. Inhibition of this enzyme leads to inhibition of inflammatory cytokine production and the production of anti-inflammatory cytokines. Also, It is demonstrated that inhibition of prolyl hydroxylase domain enzymes ۱/۲ (PHD۱/۲) increases HIF-a levels and improves the epithelial barrier following the expression of protective factors such as mucin and β-defensin. Therefore, inhibition of PDE۴B and PHD۱/۲ can be a potential therapeutic target for the treatment of IBD and the improvement of pathological symptoms in it. In this study, after Virtual Screening, Molecular Docking, and Molecular Dynamics, our results introduced ۵ compounds including Cassiamin C, Ginkgetin, Hinokiflavone, Sciadopitysin, and Sojagol as new drug candidates for the treatment of IBD. All compounds inhibit all three targets more effectively than the reference ligands, except for Sojagol, which shows lower activity against PDE۴B. Future experimental studies can validate these findings.

کلیدواژه ها:

inflammation ، inflammatory bowel disease ، anti-inflammation ، multi-target drugs