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Background: Mutations in the Spleen tyrosine kinase (Syk) protein have significant implications for its function and response to treatments. Understanding these mutations and identifying new inhibitors can lead to more effective therapies for conditions like autosomal dominant hyper-IgE syndrome (AD-HIES) and related immunological disorders. Objective: To investigate the impact of mutations in the Syk protein on its function and response to reference treatments, and to explore new inhibitors tailored to the mutational profile of Syk. Methods: We collected and analyzed mutations affecting the Syk protein to assess their functional impact. We screened 94 deleterious mutations in the kinase domain using molecular docking techniques. A library of 997 compounds with potential inhibitory activity against Syk was filtered based on Lipinski and Veber rules and toxicity assessments. We evaluated the binding affinity of reference inhibitors and 14 eligible compounds against wild-type and mutant Syk proteins. Molecular dynamics simulations were conducted to evaluate the interaction of Syk protein complexes with the reference inhibitor and potential candidate inhibitors. Results: Among the analyzed mutations, 60.5% were identified as deleterious, underscoring their potential impact on cellular processes. Virtual screening identified three potential inhibitors (IDs: 118558008, 118558000, and 118558092) with greater therapeutic potential than reference treatments, meeting all criteria and exhibiting lower IC50 values. Ligand 1 (ID: 118558000) demonstrated the most stable binding, favorable compactness, and extensive interaction with solvents. A 3D pharmacophore model was constructed, identifying structural features common to these inhibitors. Conclusion: This study found that 60.5% of reported mutations affecting the Syk protein are deleterious. Virtual screening revealed three top potential inhibitors, with ligand 1 (ID: 118558000) showing the most stable binding and favorable interactions. These inhibitors hold promise for more effective therapies targeting Syk-mediated signaling pathways. The pharmacophore model provides valuable insights for developing targeted therapies for AD-HIES and related disorders, offering hope for patients suffering from Hyper IgE syndrome with allergic symptoms., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.