Identification of potent EGFR inhibitors from TCM Database@Taiwan

Area of Science:

• Computational chemistry and pharmacology
• Drug discovery and development
• Traditional Chinese Medicine (TCM) research

Background:

• Epidermal growth factor receptor (EGFR) overexpression is linked to cancer development.
• Targeting the EGFR pathway is a strategy to inhibit cancer cell proliferation.
• Identification of novel EGFR inhibitors is crucial for cancer therapy.

Purpose of the Study:

• To identify potential EGFR inhibitors from the Traditional Chinese Medicine Database (TCM Database@Taiwan).
• To evaluate the binding affinities and interactions of identified TCM compounds with EGFR.
• To predict the bioactivity and structural compatibility of TCM candidates using computational models.

Main Methods:

• Utilized Multiple Linear Regression (MLR), Support Vector Machine (SVM), Comparative Molecular Field Analysis (CoMFA), and Comparative Molecular Similarities Indices Analysis (CoMSIA) models.
• Generated models using a training set of EGFR ligands with known inhibitory activities.
• Performed molecular docking and molecular dynamics (MD) simulations to assess binding and stability.

Main Results:

• Four TCM candidates (2-O-caffeoyl tartaric acid, Emitine, Rosmaricine, and 2-O-feruloyl tartaric acid) showed higher binding affinities than Iressa®.
• TCM candidates interacted with key residues (Asp855, Lys716, Lys728) in the EGFR protein kinase binding site.
• Validated MLR and SVM models predicted good bioactivity, and 3D-QSAR models confirmed favorable interactions with the EGFR binding site.

Conclusions:

• 2-O-caffeoyl tartaric acid, Emitine, Rosmaricine, and 2-O-feruloyl tartaric acid are identified as potential EGFR inhibitors.
• These TCM compounds demonstrate promising binding interactions and stability within the EGFR protein kinase domain.
• The study suggests these natural compounds as candidates for further investigation in cancer therapy.