Current drug targets · 2026
Discovery and Mechanistic Investigation of a Novel Kinase Inhibitor Targeting EGFR Resistance Mutations.
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Qi Lu, Chen Shuping, Zhang Ying
Аннотация
BACKGROUND: The Epidermal Growth Factor Receptor (EGFR) serves as a core target in tumor-targeted therapy. Mutations in EGFR frequently lead to resistance against clinical Tyrosine Kinase Inhibitors (TKIs), underscoring the critical need to develop novel EGFR-targeting compounds for overcoming drug resistance.
METHODS: This study performed in silico virtual screening of candidate small-molecule compounds from databases based on the common pharmacophore features of seven clinically used EGFR-TKIs. The candidates were subjected to in silico physicochemical, pharmacochemical, and toxicity evaluations, as well as in silico prediction of kinase inhibitory activity, leading to the identification of ZINC44136419 as a computationally predicted candidate. Computational cross-validation of target proteins was conducted, and EGFR was identified as the putative core target protein through enrichment, interaction network, and mutation frequency analyses. Molecular docking of ZINC44136419 with wild-type and mutant EGFR was performed in silico, using gefitinib as a control to compare docking scores.
RESULTS: A computationally predicted kinase inhibitor candidate, ZINC44136419, was obtained. In silico analyses indicated that it exhibited the core pharmacophore features of EGFR-TKIs, was predicted to meet drug-likeness criteria, showed no predicted toxicity risks, was predicted to have high synthetic feasibility, and was identified as possessing a structurally distinct scaffold (low Tanimoto similarity to known inhibitors). In silico analyses revealed predicted selective inhibitory activity against the tyrosine kinase family, with target protein enrichment analysis showing significant association with protein kinase activity, suggesting EGFR as a putative core target protein with high mutation frequency. Notably, ZINC44136419 exhibited a more favorable docking score toward mutant EGFR than toward wild-type EGFR in silico, as compared to gefitinib.
DISCUSSION: This study relies entirely on computational simulations, which carry inherent methodological limitations. Nevertheless, the favorable druggability and favorable docking scores of this compound toward mutant targets in silico may provide candidate molecules and theoretical foundations for subsequent in vitro experimental validation, delivery system development, and the design of novel agents against EGFR drug resistance.
CONCLUSION: As a computationally predicted EGFR-targeting compound, ZINC44136419 is predicted in silico to show preferential docking interactions with drug-resistant mutants through its structurally distinct scaffold, representing a preliminary candidate with potential translational value for overcoming EGFR-TKI resistance, pending experimental validation.
METHODS: This study performed in silico virtual screening of candidate small-molecule compounds from databases based on the common pharmacophore features of seven clinically used EGFR-TKIs. The candidates were subjected to in silico physicochemical, pharmacochemical, and toxicity evaluations, as well as in silico prediction of kinase inhibitory activity, leading to the identification of ZINC44136419 as a computationally predicted candidate. Computational cross-validation of target proteins was conducted, and EGFR was identified as the putative core target protein through enrichment, interaction network, and mutation frequency analyses. Molecular docking of ZINC44136419 with wild-type and mutant EGFR was performed in silico, using gefitinib as a control to compare docking scores.
RESULTS: A computationally predicted kinase inhibitor candidate, ZINC44136419, was obtained. In silico analyses indicated that it exhibited the core pharmacophore features of EGFR-TKIs, was predicted to meet drug-likeness criteria, showed no predicted toxicity risks, was predicted to have high synthetic feasibility, and was identified as possessing a structurally distinct scaffold (low Tanimoto similarity to known inhibitors). In silico analyses revealed predicted selective inhibitory activity against the tyrosine kinase family, with target protein enrichment analysis showing significant association with protein kinase activity, suggesting EGFR as a putative core target protein with high mutation frequency. Notably, ZINC44136419 exhibited a more favorable docking score toward mutant EGFR than toward wild-type EGFR in silico, as compared to gefitinib.
DISCUSSION: This study relies entirely on computational simulations, which carry inherent methodological limitations. Nevertheless, the favorable druggability and favorable docking scores of this compound toward mutant targets in silico may provide candidate molecules and theoretical foundations for subsequent in vitro experimental validation, delivery system development, and the design of novel agents against EGFR drug resistance.
CONCLUSION: As a computationally predicted EGFR-targeting compound, ZINC44136419 is predicted in silico to show preferential docking interactions with drug-resistant mutants through its structurally distinct scaffold, representing a preliminary candidate with potential translational value for overcoming EGFR-TKI resistance, pending experimental validation.