Molecular Modelling and Designing of Aminopyrimidine Derivatives as a Small Molecular Inhibitor of T790m/C797s Double Mutations in the Kinase Domain of Epidermal Growth Factor Receptor to Arrest Tumour Angiogenesis

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Abstract Introduction: Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that plays a vital role in the formation of new blood vessels from surrounding vessels, a process crucial for tumor growth, proliferation, and metastasis in cancer. Targeting EGFR is a key strategy for inhibiting angiogenesis and obstructing tumor progression. While numerous anti-EGFR drugs have been approved by the FDA and show significant benefits in maintaining patient survival rates, the emergence of mutations such as L858R, T790M, and C797S leads to resistance, limiting the efficacy of existing therapies. Materials and Methods: We employed a structure-based virtual screening (SBVS) approach using the PubChem database to identify potential aminopyrimidine derivatives. Following the screening, we utilized molecular docking and molecular dynamics simulations to assess the binding affinity, stability, and interaction of the identified compounds with the EGFR kinase domain, particularly focusing on the ATP binding site. The lead compounds were evaluated for their ability to form hydrogen bonds with key residues such as ser797 and met793. Results: The screening identified three aminopyrimidine derivatives—OS7, OS54, and OS96—that exhibited favorable binding affinity scores and a tendency to form hydrogen bonds with EGFR residues ser797 and met793. The binding free energy calculations and other predictive outcomes indicated that these compounds, especially OS7, exhibited excellent stability and stronger interactions compared to the standard drug, osimertinib. The molecular dynamics simulations revealed that OS7 maintained a stable conformation throughout the 100 ns simulation period, suggesting a better potential for targeting mutant EGFR (L858R/T790M). Conclusion: Our findings suggest that the novel aminopyrimidine derivatives, particularly OS7, could represent promising candidates for overcoming EGFR resistance, specifically targeting mutant forms like L858R/T790M. These leads demonstrate good stability and binding affinity, offering a potential avenue for the development of more effective therapies against EGFR-mutant cancers.