Evaluating Molecular Docking Accuracy: A Comparative Study with In Vitro EGFR Inhibition Data

Abstract

Cancer, particularly non-small cell lung cancer (NSCLC), remains a major global health challenge, necessitating the development of novel and more effective therapeutic agents. Epidermal growth factor receptor (EGFR) inhibitors, such as erlotinib, have shown clinical efficacy in inhibiting EGFR-mediated tumor growth. However, the emergence of resistance mechanisms and concerns regarding bioavailability highlight the need for more potent and selective EGFR inhibitors. Molecular docking has emerged as a valuable tool in the early stages of drug discovery, providing insights into ligand-receptor interactions and predicting binding affinities. This review evaluates the accuracy of molecular docking by comparing in silico binding predictions with in vitro cytotoxicity data. Erlotinib, a well-established EGFR inhibitor, serves as a reference for assessing the performance of docking simulations. We further explore the structure-activity relationship (SAR) of novel 1,3-diazetidin-2-one derivatives as potential EGFR inhibitors, highlighting key pharmacophoric features that contribute to enhanced binding and specificity. Despite the utility of docking studies, limitations such as neglecting pharmacokinetic factors and metabolic stability are discussed. The review concludes by proposing strategies to integrate docking with in vitro and in vivo testing to improve the accuracy of predictive models and optimize lead compounds for clinical development