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

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