Identification of potential inhibitors of HER2 targeting breast cancer—a structure-based drug design approach

Abstract

Breast cancer is one of the most prevalent and malignant cancers in women. Most breast cancer patients show overexpression of the HER2 protein. The current study focused on identifying potent inhibitors of HER2 using a structure-based drug design approach. Prefiltered compounds from the Drugbank and the ZINC database were docked on HER2 protein using the FlexX docking tool of LeadIT. The docking study identified the 12 best molecules that interacted strongly with the active site of HER2 and also fulfilled the ADMET parameters. The complexes of these compounds with HER2 were further subjected to molecular dynamics simulation using GROMACS 2021.4, followed by the end-state MMGBSA binding energy calculations. The RMSD analysis was conducted to study the conformational changes, which revealed stability throughout the 100 ns simulation period. The local flexibility and dynamics of the simulated ligand-protein complexes were studied using RMSF analysis. The values of the radius of gyration were computed to analyze the compactness of HER2. The MMGBSA analysis provided insights into the energetic aspects of the system. The compound DB15187 emerged as the most potent candidate, showing MMGBSA-computed binding energy of −63.60 ± 3.39 kcal/mol. The study could help develop targeted therapies for HER2-positive breast cancer.

Communicated by Ramaswamy H. Sarma

Keywords:

• Breast cancer
• HER2
• molecular docking
• ADMET
• molecular dynamics simulation

Acknowledgements

The authors would like to thank the HPC facility of IIT Delhi for providing the computational resources for the study. The authors also like to thank Thanh-Mai Pham-Thi and Dac-Nhan Nguyen for their assistance in molecular docking and for providing valuable suggestions.

Author’s contributions

GS: methodology and writing; DA: conceptualization and writing; MKA: methodology; TKC, HS, ST, and CVN: writing and reviewing; FA: methodology, writing, and editing; RP: writing, editing, and reviewing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.