Design of more potent quinazoline derivatives as EGFRWT inhibitors for the treatment of NSCLC: a computational approach

Abstract

<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Background</jats:title>
<jats:p>Lung cancer remains the leading and deadly type of cancer worldwide. It was estimated to account for about 25% of the 7 million people that died as a result of cancer-related issues/mortality every year in the world. Non-small cell lung cancer (NSCLC) is the lethal/deadly class of lung cancer with nearly 1.5 million reported cases and less than 20% survival rate. Therefore, it becomes necessary to explore more effective NSCLC drugs.</jats:p>
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<jats:title>Result</jats:title>
<jats:p>A computational approach was employed here to design ten new EGFR<jats:sup>WT</jats:sup> inhibitors using compound 18 as a template for the design identified with the best binding affinity and good pharmacokinetic properties previously reported in our work. The modeled inhibitory activities of these newly designed EGFR<jats:sup>WT</jats:sup> inhibitors (range from 7.746966 to 11.09261) were better than that of the hit compound with pIC<jats:sub>50</jats:sub> of 7.5639 and gefitinib the positive control with pIC<jats:sub>50</jats:sub> of 5.879426. The ligand-binding interaction between these newly designed EGFR<jats:sup>WT</jats:sup> inhibitors and the EGFR tyrosine kinase receptor as shown in Table 3 was investigated and elucidated using molecular docking protocol. Based on the molecular docking results, the binding affinities of these newly designed EGFR<jats:sup>WT</jats:sup> inhibitors were found to be between − 8.8 and − 9.5 kcal/mol. The designed compound SFD10 has the highest binding affinity of − 9.5 kcal/mol followed by compound SFD8 (with a binding affinity of − 9.3 kcal/mol), then by compound SFD9 and 4 (each with a binding affinity of − 9.3 kcal/mol). None of them was found to have more than one violation of the filtering criterion used in this study thereby showing good ADMET properties.</jats:p>
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<jats:title>Conclusion</jats:title>
<jats:p>The modeled inhibitory activities and binding affinities of these newly designed EGFR<jats:sup>WT</jats:sup> inhibitors were found to be higher than that of the template compound and the control (gefitinib) used in this research. They were also seen to be non-toxic with good pharmacokinetic properties.</jats:p>
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