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Nano-Differential Scanning Fluorimetry for Screening in Fragment-based Lead Discovery
Published on: May 16, 2021
Fragment-based Discovery of Potential Anticancer Lead: Computational and in vitro Studies
Abdulmalek A Balgoname1, Sufyan M Alomair1, Abdulrahman K AlMubirek1
1Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, P.O. Box 400, Al- Ahsa, 31982, Saudi Arabia.
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.
Insights
Researchers identified a novel lead compound with high affinity for HER2, a protein implicated in various cancers. This promising drug-like candidate demonstrates potential for developing new anti-cancer therapies targeting HER2.
Area of Science:
- Oncology
- Medicinal Chemistry
- Computational Biology
Background:
- The human epidermal growth factor receptor 2 (HER2) is a key driver in various cancers, including breast, lung, prostate, ovarian, and stomach cancers.
- Targeting HER2 offers a promising strategy for developing novel anticancer agents.
Purpose of the Study:
- To discover a lead scaffold with drug-like properties and high affinity for HER2.
- To identify potential therapeutic agents for HER2-driven cancers.
Main Methods:
- In silico analysis of known HER2 inhibitors, including fragmentation and molecular docking.
- Computational assessment of binding affinity, clash score, and ligand entropy.
- Development and in vitro testing of a pharmacophore model against breast, lung, and prostate cancer cell lines.
Main Results:
- The lead compound exhibited strong binding to HER2, forming hydrogen bonds with key residues (Met801, Gln99, Lys753, Thr862) and hydrophobic interactions (Leu800).
- Achieved a computational binding affinity of -13.45 kcal/mol.
- Demonstrated in vitro cytotoxic activity with IC50 values of 86.38 ±1.1 µmol/ml (MCF-7, breast), 157.02 ±1.3 µmol/ml (PC-3, prostate), and 181.1 ±2.4 µmol/ml (A-549, lung).
Conclusions:
- The identified lead compound possesses excellent drug-like characteristics.
- This compound represents a promising candidate for further development and optimization in anti-cancer drug discovery.
