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

Area of Science:

• Oncology
• Computational Chemistry
• Drug Discovery

Background:

• Breast cancer is a leading cause of cancer-related mortality in women.
• Overexpression of Human Epidermal growth factor Receptor 2 (HER2) is common in breast cancer patients.
• Targeting HER2 is a crucial strategy for developing effective breast cancer treatments.

Purpose of the Study:

• To identify potent HER2 inhibitors using a structure-based drug design approach.
• To screen and evaluate compounds for their binding affinity and drug-likeness against HER2.
• To provide potential drug candidates for HER2-positive breast cancer therapy.

Main Methods:

• Structure-based drug design utilizing docking (FlexX) and molecular dynamics (GROMACS).
• Screening of Drugbank and ZINC databases for potential HER2 inhibitors.
• ADMET parameter evaluation, RMSD, RMSF, Radius of Gyration, and MMGBSA binding energy calculations.

Main Results:

• Twelve compounds showed strong interaction with the HER2 active site and favorable ADMET properties.
• Molecular dynamics simulations confirmed the stability and conformational dynamics of ligand-HER2 complexes.
• Compound DB15187 exhibited the highest binding energy (-63.60 ± 3.39 kcal/mol), indicating potent inhibition.

Conclusions:

• Compound DB15187 is a highly promising candidate for HER2-targeted breast cancer therapy.
• The study validates structure-based drug design and computational methods for identifying novel cancer therapeutics.
• Findings pave the way for developing new targeted treatments for HER2-positive breast cancer.