Structural identification of novel pyrimidine derivatives as epidermal growth factor receptor inhibitors using 3D QSAR, molecular docking, and MMGBSA analysis: a rational approach in anticancer drug design

Abstract

Non-small cell lung cancer (NSCLC) has evolved into the deadliest in the present scenario. The progression of NSCLC is mainly due to the dysregulation of the tyrosine kinase family's epidermal growth factor receptor (EGFR). Thus, EGFR has been widely studied as a major target in the treatment of NSCLC, but the lack of selectivity and drug resistance limit the use of existing therapeutic agents. Considering the urgent necessity for the advanced development of EGFR inhibitors, we have implemented a three-dimensional structure-activity relationship (3D QSAR), molecular docking, and MMGBSA studies on a series of pyrimidine derivatives. In the 3D QSAR, the comparative molecular field analysis model (CoMFA) was obtained with a correlation coefficient (r<sup>2</sup>) = 0.698, cross-validated correlation coefficient (q<sup>2</sup>) = 0.541, and predictive r<sup>2</sup> (r<sup>2</sup><sub>pred</sub>) = 0.509. The comparative molecular similarity indices analysis (CoMSIA) model also displayed similar results with r<sup>2 </sup>= 0.72, q<sup>2 </sup>= 0.586, and r<sup>2</sup><sub>pred</sub>= 0.495. The statistical parameters fulfill the acceptability criteria of the models. Docking studies revealed the binding interactions of the pyrimidine derivatives with double mutant EGFR<sup>L858R/T790M</sup>. Docking scores of the top two selected compounds 29 and 34 were 92.99 and 92.13, respectively. Analyzing 3D QSAR contour plots and docking results reviewed some important structural attributes of EGFR <sup>L858R/T790M</sup> selective inhibitors, which directed the designing of some new molecules. The designed compounds showed good predictive activity and exhibited higher binding interactions with EGFRL858R/T790M than the reference ligand gefitinib. Moreover, to evaluate the binding of selected top hits from docking and designed compounds, MMGBSA (Molecular Mechanics-Generalized Born Surface Area) analysis was performed, which revealed that the designed compound (N7) showed a good binding affinity with EGFR<sup>L858R/T790M</sup> (dG = -68.59 kcal/mol) as compared to other compounds. Further, in silico ADME predictions revealed the drug-likeness of the designed compounds. Thus, this work will guide researchers in future developments of pyrimidine derivatives as EGFR inhibitors.