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

Abstract

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 prostat-ic cancer cell lines. Results: The discovered lead compound achieved several hydrogen bonds with the primary resi-dues 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.