Characterization of Novel Anticancer Agent using Computer-Aided Drug Discovery Processes Reveals Selective Interaction with the Epidermal Growth Factor Receptor

Background : The traditional drug discovery process for anticancer drugs is hindered by prolonged screening and off-target effects. To address these challenges, we screened three novel compounds for their anticancer activity and employed computer-aided drug design to evaluate lead compounds' pharmacological properties and molecular interactions. This study aimed to determine the anticancer potential of our compounds and predict the targets of the lead compound using computer-aided drug discovery processes. Method : Three synthetic compounds (compounds 1,2, and 3) were tested for cytotoxicity against four cancer cell lines. Using the STRING, protein-protein interactions were analysed, and functional enrichment analyses were performed using Metascape. Molecular docking, dynamic simulations, pharmacological ADME properties, and drug-likeness properties were assessed using GOLD, Amber 22, ADMETLab, and SWISSADME software packages. Results : Compound 2 inhibited MDA MB 468 and MDA MB 231 cell proliferation and showed good selectivity against PNT2 cells. Pathway analysis associated Compound 2 with cancer and focal adhesion pathways, identifying potential targets for EGFR, AKT1, and VEGFR2. Molecular docking revealed that Compound 2 binds to the ATP-binding activation site at Lys745 and the DFG motif at Asp855 of EGFR, as well as the ATP binding site of VEGFR2 at Cys919 and Phe918. Molecular dynamic simulations indicated that EGFR had the most energetically stable protein-ligand interactions, followed by VEGFR2 and AKT1. EGFR also showed flexible amino acid residues and strong hydrogen bond interactions. This study highlighted that Compound 2 showed significant cytotoxicity against breast cancer cell lines and is linked to cancer pathways, notably ErbB and EGFR. Compound 2 also binds to the ATP activation site and DFG motif of EGFR in docking studies and may have an energetically stable interaction with EGFR. Conclusion : This highlight Compound 2 as anticancer agent with the potential to interact with EGFR.