Rational design of novel potential EGFR inhibitors by 3D-QSAR, molecular docking, molecular dynamics simulation, and pharmacokinetics studies

The epidermal growth factor receptor (EGFR) is one of the most attractive drug targets against the human pancreas cancer cell line (Panc-1). In this research, forty xanthine derivatives previously identified as novel potential EGFR inhibitors were subjected to 3D-QSAR studies in order to design new compounds with high predicted activity. The generated models showed satisfactory statistical results and provided useful insights by analyzing the graphical contour maps, revealing the structural requirements that influence the activity. Consequently, four new compounds with high inhibitory activity were designed. Subsequently, molecular docking and molecular dynamics (MD) simulations of 100 ns were employed to investigate the interaction mechanism and conformational changes of the newly designed compounds at the binding site of EGFR. Moreover, these compounds were checked for in-silico pharmacokinetics prediction parameters for wet-lab applicability, showing good ADMET properties and bioavailability. The present findings might ultimately contribute to the future development of potent EGFR inhibitors.