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Updated: Jan 19, 2026
Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
Published on: December 5, 2017
In-silico Design, ADMET Screening, MM-GBSA Binding Free Energy of Some Novel Isoxazole Substituted 9-Anilinoacridines
Rajagopal Kalirajan1, Arumugasamy Pandiselvi1, Byran Gowramma1
1Department of Pharmaceutical Chemistry, JSS College of Pharmacy, A Constituent College of JSS Academy of Higher Education & Research-(Deemed to be University), Udhagamandalam - 643001 (Tamilnadu), India.
Background:
Human Epidermal development factor Receptor-2 (HER2) is a membrane tyrosine kinase which is overexpressed and gene amplified in human breast cancers. HER2 amplification and overexpression have been linked to important tumor cell proliferation and survival pathways for 20% of instances of breast cancer. 9-aminoacridines are significant DNA-intercalating agents because of their antiproliferative properties.
Objective:
Some novel isoxazole substituted 9-anilinoacridines(1a-z) were designed by in-silico technique for their HER2 inhibitory activity. Docking investigations of compounds 1a-z are performed against HER2 (PDB id-3PP0) by using Schrodinger suit 2016-2.
Methods:
Molecular docking study for the designed molecules 1a-z are performed by Glide module, in-silico ADMET screening by QikProp module and binding free energy by Prime-MMGBSA module of Schrodinger suit. The binding affinity of designed molecules 1a-z towards HER2 was chosen based on GLIDE score.
Results:
Many compounds showed good hydrophobic communications and hydrogen bonding associations to hinder HER2. The compounds 1a-z, aside from 1z have significant Glide scores in the scope of - 4.91 to - 10.59 when compared with the standard Ethacridine (- 4.23) and Tamoxifen (- 3.78). The in-silico ADMET properties are inside the suggested about drug likeness. MM-GBSA binding of the most intense inhibitor is positive.
Conclusion:
The outcomes reveal that this study provides evidence for the consideration of isoxazole substituted 9-aminoacridine derivatives as potential HER2 inhibitors. The compounds, 1s,x,v,a,j,r with significant Glide scores may produce significant anti breast cancer activity and further in vitro and in vivo investigations may prove their therapeutic potential.
Insights
Novel isoxazole-substituted 9-aminoacridines were designed as potential inhibitors of Human Epidermal growth factor Receptor-2 (HER2) for breast cancer treatment. Computational studies indicate promising HER2 inhibitory activity and favorable drug-like properties for these compounds.
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Oncology
Background:
- Human Epidermal growth factor Receptor-2 (HER2) is a key target in breast cancer, implicated in tumor cell proliferation and survival in 20% of cases.
- 9-aminoacridines are known for their antiproliferative properties due to DNA intercalation.
Purpose of the Study:
- To design novel isoxazole-substituted 9-anilinoacridines with potential HER2 inhibitory activity using in-silico methods.
- To evaluate the binding affinity and drug-likeness of these designed compounds against HER2.
Main Methods:
- In-silico design and molecular docking of isoxazole-substituted 9-anilinoacridines (compounds 1a-z) against HER2 (PDB ID: 3PP0) using Schrodinger Suite 2016-2.
- ADMET property prediction using the QikProp module and binding free energy calculations using the Prime-MMGBSA module.
- Evaluation of binding affinity based on GLIDE scores.
Main Results:
- Compounds demonstrated favorable hydrophobic interactions and hydrogen bonding with HER2.
- Most compounds exhibited significant Glide scores (-4.91 to -10.59), outperforming Ethacridine and Tamoxifen.
- In-silico ADMET properties suggested good drug-likeness, with positive MM-GBSA binding energy for the most potent inhibitors.
Conclusions:
- Isoxazole-substituted 9-aminoacridine derivatives show potential as HER2 inhibitors.
- Compounds 1s, 1x, 1v, 1a, 1j, and 1r possess significant Glide scores and may exhibit anti-breast cancer activity.
- Further in vitro and in vivo studies are warranted to confirm the therapeutic potential of these compounds.
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