Discovery of Novel Epidermal Growth Factor Receptor (EGFR) Inhibitors Using Computational Approaches

• Published in: Journal of chemical information and modeling 2022-11, Vol.62 (21), p.5149-5164
• Main Authors: Huo, Donghui, Wang, Shiyu, Kong, Yue, Qin, Zijian, Yan, Aixia
• Format: Article
• Language: English
• Subjects: Cell Proliferation; Computational Chemistry; Epidermal growth factor; ErbB Receptors - chemistry; Growth factors; Inhibitors; Ligands; Molecular Docking Simulation; Molecular dynamics; Protein Kinase Inhibitors - chemistry; Quantitative Structure-Activity Relationship; Receptors; Screening
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.1c00884

The epidermal growth factor receptor (EGFR) signaling pathway plays an important role in cell growth, proliferation, differentiation, and other physiological processes, which makes the EGFR a promising target for anticancer therapies. The discovery of novel EGFR inhibitors may provide a solution to the problem of drug resistance. In this work, we performed a ligand-based virtual screening (LBVS) protocol for finding novel EGFR inhibitors from a 5.3 million compound library. First, the 3D shape-based similarity was used to obtain structurally novel EGFR inhibitors. In this study, we tried three queries; two were crystal structures and one was generated from deep generative models of graphs (DGMG). Next, we have built four structure–activity relationship (SAR) models and three quantitative structure–activity relationship (QSAR) models based on an SVM method for further screening of highly active EGFR inhibitors. Experimental validations led to the identification of nine hits out of 18 tested compounds. Among them, hit 1, hit 5, and hit 6 had IC50 values around 80 nM against EGFR whose interactions with EGFR were further investigated by molecular dynamics simulations.