Genotype–phenotype correlation in IBD: unveiling putative inhibitors for IL10RA and IRF5 variants—an in silico analysis

Despite recent advances, the majority of the susceptibility genes for inflammatory bowel disease (IBD), a chronic inflammatory disorder that affects the gastrointestinal tract and is commonly diagnosed as Crohn disease and ulcerative colitis, are still unknown. Empirical data indicate that the human interleukin-10 receptor subunit alpha (IL10RA) mutation could impact the regulation of the gut inflammatory response, with interferon regulatory factor 5 (IRF5) being a key player in controlling mucosal inflammation in IBD. Notably, aloin, andrographolide, incensole, and curcumin show up as leading contenders that are significantly contributing to anti-inflammation and a natural adjuvant therapy for IBD. Nevertheless, the exact chemical process by which these substances block IL10RA and IRF5 is still unknown. To close this gap, we carried out molecular interaction and molecular dynamics (MD) simulation experiments to understand how synthetic and herbal drugs interact with IL10RA and IRF5 variants. Molecular docking experiments have demonstrated that aloin (−9.028/−8.12 kcal/mol) has the highest binding affinities when compared to mesalazine (−8.22/−8.615 kcal/mol), a synthetic drug. The study discusses the promising inhibitory effects of aloin and mesalazine on IL10RA and IRF5 variants, supported by structural studies and root mean square fluctuation (RMSF) analysis indicating the stability of aloin. Additionally, drug-likeness was evaluated through Pre-ADMET annotation, while pharmacokinetics analysis facilitated the calculation of binding energies. Integrated molecular docking and simulation studies suggest the potential of aloin with IBD variants. The findings demonstrate that analyzing phenotypic correlations aids in understanding IBD variants. Structural analysis of IL10RA and IRF5 proteins indicates how differences lead to functional abnormalities. This is a step toward personalized IBD treatment by multidimensional screening and herbal therapy.