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

Author(s): Abdulmalek A. Balgoname*, Sufyan M. Alomair, Abdulrahman K. AlMubirek, Mohammed A. Khedr*

Journal Name: Current Computer-Aided Drug Design

Volume 17 , Issue 3 , 2021

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Graphical 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 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.

Keywords: Fragment-based, virtual screening, HER-2, docking, dynamic simulation, in vitro cytotoxic effect.

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Article Details

Year: 2021
Published on: 20 June, 2020
Page: [421 - 428]
Pages: 8
DOI: 10.2174/1573409916666200620195025
Price: $65

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