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Computational analyses of curcuminoid analogs against kinase domain of HER2
Wannarat Yim-im, Orathai Sawatdichaikul1, Suwanna Semsri
1Institute of Food Research and Product Development, Kasetsart University, 50 Ngam Wong Wan Rd, Chatuchak, Bangkok 10900, Thailand. ifrots@ku.ac.th.
Background:
Human epidermal growth factor receptor 2 (HER2) has an important role in cancer aggressiveness and poor prognosis. HER2 has been used as a drug target for cancers. In particular, to effectively treat HER2-positive cancer, small molecule inhibitors were developed to target HER2 kinase. Knowing that curcumin has been used as food to inhibit cancer activity, this study evaluated the efficacy of natural curcumins and curcumin analogs as HER2 inhibitors using in vitro and in silico studies. The curcumin analogs considered in this study composed of 4 groups classified by their core structure, β-diketone, monoketone, pyrazole, and isoxazole.
Results:
In the present study, both computational and experimental studies were performed. The specificity of curcumin analogs selected from the docked results was examined against human breast cancer cell lines. The screened curcumin compounds were then subjected to molecular dynamics simulation study. By modifying curcumin analogs, we found that protein-ligand affinity increases. The benzene ring with a hydroxyl group could enhance affinity by forming hydrophobic interactions and the hydrogen bond with the hydrophobic pocket. Hydroxyl, carbonyl or methoxy group also formed hydrogen bonds with residues in the adenine pocket and sugar pocket of HER2-TK. These modifications could suggest the new drug design for potentially effective HER2-TK inhibitors. Two outstanding compounds, bisdemethylcurcumin (AS-KTC006) and 3,5-bis((E)-3,4-dimethoxystyryl)isoxazole (AS-KTC021 ),were well oriented in the binding pocket almost in the simulation time, 30 ns. This evidence confirmed the results of cell-based assays and the docking studies. They possessed more distinguished interactions than known HER2-TK inhibitors, considering them as a promising drug in the near future.
Conclusions:
The series of curcumin compounds were screened using a computational molecular docking and followed by human breast cancer cell lines assay. Both AS-KTC006 and AS-KTC021 could inhibit breast cancer cell lines though inhibiting of HER2-TK. The intermolecular interactions were confirmed by molecular dynamics simulation studies. This information would explore more understanding of curcuminoid structures and HER2-TK.
Insights
Natural curcumins and their analogs show promise as HER2 inhibitors for breast cancer treatment. Computational and in vitro studies identified specific compounds that effectively inhibit HER2 kinase activity, suggesting potential for new drug development.
Area of Science:
- Medicinal Chemistry
- Computational Biology
- Oncology
Background:
- Human epidermal growth factor receptor 2 (HER2) is a key driver of cancer aggressiveness and a validated drug target.
- HER2-positive cancers often exhibit poor prognosis, necessitating novel therapeutic strategies.
- Curcumin, a natural compound, has demonstrated anti-cancer properties, prompting investigation into its derivatives as targeted inhibitors.
Purpose of the Study:
- To evaluate the efficacy of natural curcumins and their analogs as inhibitors of HER2 kinase.
- To identify specific structural modifications that enhance the inhibitory activity of curcumin analogs against HER2.
- To explore the potential of these compounds as therapeutic agents for HER2-positive cancers.
Main Methods:
- In silico molecular docking and molecular dynamics simulations were employed to screen and analyze curcumin analogs.
- In vitro studies using human breast cancer cell lines assessed the specificity and efficacy of selected compounds.
- Structure-activity relationships were investigated by modifying curcumin analog core structures (β-diketone, monoketone, pyrazole, isoxazole).
Main Results:
- Computational and experimental studies identified potent HER2 inhibitors among curcumin analogs.
- Structural modifications, such as incorporating benzene rings with hydroxyl groups, enhanced protein-ligand affinity through hydrophobic and hydrogen bonding interactions.
- Two compounds, bisdemethylcurcumin (AS-KTC006) and 3,5-bis((E)-3,4-dimethoxystyryl)isoxazole (AS-KTC021), demonstrated significant HER2-TK inhibition and sustained binding.
- These compounds exhibited superior interactions compared to existing HER2-TK inhibitors.
Conclusions:
- Curcumin analogs, particularly AS-KTC006 and AS-KTC021, effectively inhibit HER2-TK and breast cancer cell lines.
- Molecular dynamics simulations confirmed the intermolecular interactions responsible for HER2-TK inhibition.
- This study provides valuable insights into curcuminoid structures for developing novel HER2-TK inhibitors.
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