Hybrid Pharmacophore- and Structure-Based Virtual Screening Pipeline to Identify Novel EGFR Inhibitors That Suppress Non-Small Cell Lung Cancer Cell Growth

• Published in: International journal of molecular sciences 2022-03, Vol.23 (7), p.3487
• Main Authors: Weng, Chia-Wei, Wei, Chi-Hsuan, Tsai, Jeng-Yuan, Lai, Yi-Hua, Chang, Gee-Chen, Chen, Jeremy J W
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Binding sites; Carcinoma, Non-Small-Cell Lung - pathology; Cell growth; Cell Line, Tumor; Drug development; Drug Resistance, Neoplasm; EGFR inhibitor; Enzyme-linked immunosorbent assay; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - metabolism; Gefitinib; Growth factors; Humans; Hydrogen bonds; Ligands; Lung cancer; Lung Neoplasms - metabolism; Metastases; Molecular docking; Molecular Docking Simulation; Mutation; Non-small cell lung carcinoma; Pharmacology; pharmacophore model; Pharmacophores; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Signal transduction; Structure-activity relationships; Tyrosine; virtual screening; Workflow
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23073487

Dysregulated epidermal growth factor receptor (EGFR) expression is frequently observed in non-small cell lung cancer (NSCLC) growth and metastasis. Despite recent successes in the development of tyrosine kinase inhibitors (TKIs), inevitable resistance to TKIs has led to urgent calls for novel EGFR inhibitors. Herein, we report a rational workflow used to identify novel EGFR-TKIs by combining hybrid ligand- and structure-based pharmacophore models. Three types of models were developed in this workflow, including 3D QSAR-, common feature-, and structure-based EGFR-TK domain-containing pharmacophores. A National Cancer Institute (NCI) compound dataset was adopted for multiple-stage pharmacophore-based virtual screening (PBVS) of various pharmacophore models. The six top-scoring compounds were identified through the PBVS pipeline coupled with molecular docking. Among these compounds, NSC609077 exerted a significant inhibitory effect on EGFR activity in gefitinib-resistant H1975 cells, as determined by an enzyme-linked immunosorbent assay (ELISA). Further investigations showed that NSC609077 inhibited the anchorage-dependent growth and migration of lung cancer cells. Furthermore, NSC609077 exerted a suppressive effect on the EGFR/PI3K/AKT pathway in H1975 cells. In conclusion, these findings suggest that hybrid virtual screening may accelerate the development of targeted drugs for lung cancer treatment.