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Molecular docking and MD simulation approach to identify potential phytochemical lead molecule against triple
Pranaya Sankaranarayanan1, Dicky John Davis G1, Abhinand Pa1
1Department of Bioinformatics, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Chennai, Tamil Nadu, 600116, India.
Background:
Triple-negative breast cancers (TNBC) are defined as tumors that lack the expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). It exhibits unique clinical and pathological features, demonstrates high aggressiveness, and has a relatively poor prognosis and clinical outcome.
Objective:
To identify a novel drug target protein against TNBC and potential phytochemical lead molecules against the identified target.
Methods:
In this study, we retrieved TNBC samples from NGS and microarray datasets in the Gene Expression Omnibus database. We employed a combination of differential gene expression studies, protein-protein interaction analysis, and network topology investigation to identify the target protein. Additionally, the molecular docking and molecular dynamics (MD) simulation studies followed by Molecular Mechanics with Generalised Born Surface Area salvation was used to identify potential lead molecule.
Result:
The upregulated genes with LogFC > 1.25 and P-value < 0.05 from the TNBC gene expression dataset were identified. Androgen receptor (AR) was found to be an appropriate hub target in the protein-protein interaction network. Phytochemicals that inhibit breast cancer target were retrieved from the PubChem database and virtual screening was performed using PyRx against the AR protein. Thereby, the AR was found to be the target protein and 2-hydroxynaringenin was discovered to be a possible phytochemical lead molecule for combating TNBC. Moreover, the AR and the 2-hydroxynaringenin complex showed structural stability and higher binding affinity through molecular dynamics and MM-GBSA studies.
Conclusion:
AR was identified as a hub protein that is highly expressed in breast cancer and 2-hydroxynaringenin efficacy of counter TNBC requires further investigation both in vitro and in vivo.
Insights
Researchers identified Androgen Receptor (AR) as a key target for triple-negative breast cancer (TNBC). They also found 2-hydroxynaringenin as a potential phytochemical to combat TNBC, showing promising binding affinity in simulations.
Area of Science:
- Oncology
- Computational Biology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) lacks ER, PR, and HER2 receptors.
- TNBC is characterized by high aggressiveness and poor prognosis.
- Novel therapeutic targets and treatments for TNBC are urgently needed.
Purpose of the Study:
- Identify a novel drug target protein for TNBC.
- Discover potential phytochemical lead molecules against the identified target.
Main Methods:
- Utilized Gene Expression Omnibus datasets for differential gene expression analysis.
- Employed protein-protein interaction and network topology analysis to identify hub proteins.
- Conducted molecular docking, dynamics, and MM-GBSA simulations to screen phytochemicals.
Main Results:
- Androgen Receptor (AR) was identified as a significant hub target in TNBC.
- Virtual screening identified 2-hydroxynaringenin as a potential lead molecule targeting AR.
- Molecular dynamics and MM-GBSA studies confirmed structural stability and high binding affinity of the AR-2-hydroxynaringenin complex.
Conclusions:
- AR is a promising therapeutic target for TNBC.
- 2-hydroxynaringenin demonstrates potential as a phytochemical agent against TNBC.
- Further in vitro and in vivo studies are required to validate the efficacy of 2-hydroxynaringenin for TNBC treatment.
