Background: The human epidermal growth factor receptor 2 (HER2) plays a role in the
propagation of different types of cancers. It was identified in many types of cancer tissues like;
breast, ovarian, lung, prostate, and stomach cancers. Therefore, inhibition of HER2 can lead to the
discovery of novel anticancer agents.
Objective: The study aims to discover a lead scaffold with drug-like properties and high affinity
Methods: A list of HER2 inhibitors were collected, analyzed, and subjected to fragmentation and
molecular docking. The in silico study computed the affinity, clash score, and ligand entropy score.
A pharmacophore model for an ideal inhibitor designed, and tested against breast, lung, and prostatic
cancer cell lines.
Results: The discovered lead compound achieved several hydrogen bonds with the primary residues
found in the active site of HER2, such as; Met801, Gln99, Lys753, and Thr862 with a computational
affinity – 13.45 kcal/mol. In addition to a hydrophobic interaction with leu800. The in vitro
cytotoxic activity against; breast cancer MCF-7, prostatic cancer PC-3 and lung cancer A-549 cell
lines showed (IC50 = 86.38 ±1.1 mmol/ml), (IC50 = 157.02 ±1.3 mmol/ml), and (IC50 = 181.1
±2.4 mmol/ml) respectively.
Conclusion: The discovered lead is an excellent drug-like candidate for further development and