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Virtual screening of FOXO3a activators from natural product-like compound library
Suryaa Manoharan1, Kunjkumar Prajapati1, Tharini Karthikeyan2
1Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore, 641 046, India.
Abstract:
FOXO3a is an inevitable transcription factor, which is involved in the regulation of biological processes such as proliferation, DNA damage repair, cell cycle arrest and cell death. Previous studies confirmed that FOXO3a is an excellent tumor suppressor and in cancer cells, it gets phosphorylated followed by proteasomal degradation. FOXO3a is found to be inactivated in cancer cells, whereas in normal cells it gets activated and upregulates its downstream targets, which induces apoptotic pathways. Hence, activation of FOXO3a can be implicated in cancer prevention and treatment. A variety of commercially available FOXO3a activators such as doxorubicin and metformin possess undesirable adverse effects to normal cells and tissues, which are their major limitations. Natural bioactive compounds, eliminating the limitations of such compounds, become an excellent choice for the treatment and prevention of cancer. In this study, a library of natural product-like compounds was screened for their FOXO3a activation potential through in silico approach, which included the use of several bioinformatics tools and processes. Other molecular interaction studies as well as binding and specificity studies were carried out with the help of molecular dynamics simulation. Virtual screening of 7700 small molecules from the Natural Products-like Compound Library revealed the top three FOXO3a activators F3385-6269, F2183-0033 and F3351-0330. Further validation studies are warranted to confirm these findings.
Insights
This study identified novel natural compounds that activate FOXO3a, a key tumor suppressor. These compounds show promise for cancer prevention and treatment, offering a safer alternative to existing therapies.
Area of Science:
- Molecular Biology
- Biochemistry
- Computational Biology
Background:
- FOXO3a is a crucial transcription factor involved in cell proliferation, DNA repair, cell cycle arrest, and apoptosis.
- FOXO3a acts as a tumor suppressor, becoming inactivated in cancer cells via phosphorylation and proteasomal degradation.
- Activating FOXO3a can induce apoptotic pathways, making it a target for cancer prevention and treatment.
Purpose of the Study:
- To screen a library of natural product-like compounds for FOXO3a activation potential using in silico methods.
- To identify novel, safe FOXO3a activators as potential cancer therapeutics.
- To overcome the limitations of existing FOXO3a activators with adverse side effects.
Main Methods:
- In silico screening of 7700 small molecules from a Natural Products-like Compound Library.
- Utilized bioinformatics tools and processes for initial compound evaluation.
- Employed molecular dynamics simulations for binding and specificity studies.
Main Results:
- Identified three top FOXO3a activators: F3385-6269, F2183-0033, and F3351-0330.
- The virtual screening demonstrated the potential of these natural compounds to modulate FOXO3a activity.
- Molecular dynamics simulations provided insights into the binding and specificity of the identified compounds.
Conclusions:
- The identified compounds (F3385-6269, F2183-0033, F3351-0330) are promising candidates for FOXO3a activation.
- These natural compounds may offer a safer therapeutic strategy for cancer prevention and treatment.
- Further experimental validation is necessary to confirm the efficacy and safety of these identified FOXO3a activators.
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