Modeling study, 3D-QSAR and molecular docking of 9H-purine derivatives as EGFR inhibitors

Abstract

New therapeutic strategies, called targeted therapies, are now possible thanks to recent advances in oncology. These treatments more specifically reach cancer cells by disrupting the biological mechanisms that lead to their multiplication: they essentially act at the level of growth factor receptors. Tyrosine kinase inhibitors are small molecules that act specifically inside tumor cells by blocking the activation of tyrosine kinases. They are part of the new generation of anti-cancer drugs called targeted therapies. Using the tools of theoretical chemistry and drug design techniques, we constructed a structure–activity relationship model (3D-QSAR) based on the pharmacophore of a series of 9H-purine derivatives taken from the literature, whose EGFR inhibitors are quantitatively known. The QSAR model obtained, which is statistically satisfactory, will be used, on the one hand, to study the structural characteristics responsible for EGFR inhibition and, on the other hand, to predict structures of the same chemical family having a better activity on this protein kinase.We then performed the molecular docking protocol on the molecules considered relevant due to their activity on EGFR. This study aims to enrich the interpretations extracted from the contour maps of the 3D-QSAR model and to search in silico for the most favorable mode of interaction of these inhibitors within the receptor (PDB: 5XGN).The theoretical approaches used in our research should help to better understand the mechanisms involved in the ligand/receptor interaction and, ultimately, to rationalize the design of new molecules for therapeutic purposes.