Bioinformatics-driven discovery of novel EGFR kinase inhibitors as anti-cancer therapeutics: In silico screening and...

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Oncology

Background:

• Epidermal growth factor receptor (EGFR) inhibitors are standard first-line treatment for EGFR-mutated non-small-cell lung cancer (NSCLC).
• Acquisition of the T790M mutation leads to drug resistance, necessitating novel therapeutic strategies.

Purpose of the Study:

• To identify novel EGFR-tyrosine kinase inhibitors (TKIs) targeting the T790M resistance mutation in NSCLC.
• To discover new compounds with therapeutic potential against lung cancer harboring specific EGFR mutations.

Main Methods:

• Receptor-based virtual screening of the ChemDiv diversity database.
• Molecular docking using AutoDock 4.0 and AutoDock Vina 1.1.2.
• Post-docking analysis, including MM/PBSA per-residue energy decomposition.
• Biological evaluation of hit compounds for EGFR auto-phosphorylation inhibition and apoptosis induction.

Main Results:

• Four compounds were identified that bind to the ATP-binding region of EGFR-TK.
• Ligands exhibited hydrophobic interactions, hydrogen bonding with Met793, and π-cation interactions with Lys745.
• Key residues contributing to binding energy included Val726, Leu792, Met793, Gly796, Cys797, Leu798, and Thr844.
• Hit compounds suppressed EGFR auto-phosphorylation and induced selective apoptosis in lung cancer cells with EGFR L858R/T790M mutations.

Conclusions:

• The study identified novel EGFR-TKIs with potential therapeutic efficacy against NSCLC harboring the T790M resistance mutation.
• The discovered compounds demonstrate promising activity and warrant further investigation for lung cancer treatment.