Fragment-based Discovery of Potential Anticancer Lead: Computational and in vitro Studies.

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 toward HER2.

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 optimization.