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  4. Volume 21, Issue 19
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Volume 21, Issue 19
  • ISSN: 1570-1808
  • E-ISSN: 1875-628X

Abstract

Background

Breast cancer is the most common cancer in women. Tyrosine kinase inhibitors were developed to treat breast cancer. EGFR/ErbB1 inhibition has proved to be a promising target in breast carcinoma therapy. Drugs with benzimidazole nucleus have been approved by the FDA for cancer treatment.

Objective

To design and develop benzimidazole anticancer small molecules for EGFR inhibition for the treatment of breast cancer.

Methods

By 3D-QSAR-based virtual screening, molecular docking, molecular simulation and drug likeness study.

Results

In this research, a 3D-QSAR pharmacophore was generated with four salient features. Namely H-bond acceptor (HBA), two ring aromatic (RA) and hydrophobic (HY) features. Its correlation-coefficient (r) is 0.8412, RMSD of 0 .96 and with 32.84 bits cost difference value. With virtual screening, 4 top hits were identified. Novel benzimidazole derivatives were designed (1a-l) by using the features of hit molecules and the pharmacophore. The novel designed small molecules that were druggable as they passed the Lipinski and Veber rule. Novel ligands and EGFR protein interaction were good. 1a and 1i were found to be the best-designed molecules. They had -8.6 Kcal/mol and -8.4 Kcal/mol docking interaction energy, respectively, whereas Compound 4 (reference) scored -7.4 Kcal/mol. Both these molecules were stable inside the binding pocket of the EGFR protein. The molecular dynamic simulation study revealed that 1a attained equilibrium at 0.15nm.

Conclusion

In silicon novel benzimidazole small molecules were designed and developed as EGFR inhibitors to treat breast cancer.

© 2024 Bentham Science Publishers
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2025-01-10
2025-06-19

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Development of Benzimidazole Anticancer Leads for EGFR Inhibition by 3D-QSAR Based Virtual Screening, Molecular Docking, Molecular Simulation and Drug Likeness Study
Letters in Drug Design & Discovery 21, 4833 (2024); https://doi.org/10.2174/0115701808344738241231072218
/content/journals/lddd/10.2174/0115701808344738241231072218
/content/journals/lddd/10.2174/0115701808344738241231072218
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  • Article Type:     Research Article
Keyword(s): benzimidazole; breast cancer; docking; EGFR; pharmacophore; simulation

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