article · ACS Omega
Computational modelling and quantitative structure-activity relationship techniques guided the design of 18 novel quinazoline derivatives targeted against the epidermal growth factor receptor for lung cancer treatment. Introducing electronegative substituents at the N-3 and C-6 positions of the quinazoline ring established favourable polar interactions and hydrophobic contacts within the receptor ATP-binding pocket, boosting predicted inhibitory performance against lung cancer cell lines. Computational evaluation of absorption, distribution, metabolism, excretion, and toxicity showed that all 18 proposed candidates possessed strong drug-like profiles. Detailed molecular docking analyses on selected candidates, namely Pred15, Pred17, Pred20, and Pred21, demonstrated high binding affinity to the target protein. Molecular dynamics simulations further established the physical stability and binding characteristics of Pred17, Pred20, and Pred21, marking them as viable candidate inhibitors for therapeutic development.
Lung cancer remains a leading cause of cancer mortality worldwide, often requiring treatments that disrupt specific tumour-promoting proteins such as EGFR. Computational design techniques enable researchers to rapidly screen and refine new chemical compounds before undertaking costly laboratory synthesis. Identifying robust candidate molecules through computer simulations helps accelerate the discovery pipeline for targeted cancer therapies.
This research provides computational lead candidates that could be licensed or adopted by pharmaceutical companies and oncology drug discovery teams seeking new EGFR inhibitors. Because the findings are based entirely on in silico QSAR, docking, and molecular dynamics models, the technology is at a very early discovery stage. Significant wet-lab synthesis, cellular testing, and preclinical trials are necessary before any therapeutic application can be realised.
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-randomization, and applicability domain validations. Leveraging the predictions from the QSAR model, we designed 18 new molecules based on the modifications at the N-3 and C-6 positions of the quinazoline ring, with electronegative substituents at these positions fostering optimal polar interactions and hydrophobic contacts within the ATP-binding site of EGFR, significantly enhancing the inhibitory activity against the lung cancer cell line. Subsequently, ADMET predictions were conducted for these 18 compounds, revealing outstanding ADMET profiles. Molecular docking analyses were performed to investigate the interactions between the newly designed molecules-Pred15, Pred17, Pred20, Pred21-and the EGFR protein, indicating high affinity of these proposed compounds to EGFR. Furthermore, molecular dynamics (MD) simulations were utilized to assess the stability and binding modes of compounds Pred17, Pred20, and Pred21, reinforcing their potential as novel inhibitors against human lung cancer. Overall, our findings suggest that these investigated compounds can serve as effective inhibitors, showcasing the utility of our analytical and design approach in the identification of promising therapeutic agents.
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DOI: 10.1021/acsomega.4c04639
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