Hybrid Pharmacophore- and Structure-Based Virtual Screening Pipeline to Identify Novel EGFR Inhibitors That Suppress Non-Small Cell Lung Cancer Cell Growth.
Chia-Wei WengChi-Hsuan WeiJeng-Yuan TsaiYi-Hua LaiGee-Chen ChangJeremy J W ChenPublished in: International journal of molecular sciences (2022)
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.
Keyphrases
- epidermal growth factor receptor
- molecular docking
- small cell lung cancer
- tyrosine kinase
- advanced non small cell lung cancer
- molecular dynamics
- molecular dynamics simulations
- induced apoptosis
- cell cycle arrest
- poor prognosis
- brain metastases
- cell proliferation
- cancer therapy
- machine learning
- oxidative stress
- endoplasmic reticulum stress
- electronic health record
- chronic myeloid leukemia