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Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammation and joint destruction. Various genetic studies have identified 100 susceptible genes linked with RA. Among them, four SNPs (rs6671847, rs1801274, rs17400517, and rs6668534) in the FCGR2A gene have been shown to be associated with RA susceptibility. The functional consequences of these pathogenic variants on the protein structure, stability, and interaction with other molecules remain unknown. In this study, we used multiple in silico methods to examine the effects of these mutations on the FCGR2A gene. We annotated the gene structurally, functionally, and Predicted physiochemical characterization, gene expression profiling, and Post-translational modification (PTM) analysis. We found that the (rs1801274 H167R) mutation in FCGR2A had a significant effect on the protein structure and interactions, whereas the other three SNPs (rs6671847, rs17400517, and rs6668534) had no significant impact on protein function. We also performed protein-protein interaction and molecular docking studies to identify potential therapeutic targets for RA. Our structure-based analysis showed that these mutations affect the protein core regions and functional domains, leading to altered protein-protein interactions both directly and indirectly. We identified three novel potential target sites for the development of drugs to treat RA by developing a drugability profile. These findings may have significant implications for the pathogenesis of RA and can be validated further through in vitro studies. Our study demonstrates the potential utility of multidirectional computational analysis for screening clinically relevant mutations in RA before undertaking biological assays. The findings highlight the importance of understanding the structural and functional consequences of pathogenic variants for developing effective therapeutic strategies. Overall, the insights gained from our in-silico approaches could aid in the development of novel therapies for RA and could pave the way for modified medicine in the treatment of this complex disease.
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