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Exploring the Synergistic Mechanism of AP2A2 Transcription Factor Inhibition via Molecular Modeling and Simulations
Vidya Niranjan1, Anagha S Setlur2, Chandrashekar K2
1Department of Biotechnology, RV College of Engineering, Bangalore, 560059, India. vidya.n@rvce.edu.in.
Abstract:
Studies have shown that transcription factor AP2A2 (activator protein-2 alpha-2) is involved in the expression of DLEC1, a tumor suppressor gene, which, when mutated, will cause breast cancer and is thus an excellent target for breast cancer studies. Therefore, in the present research, a synergistic approach toward combating breast cancer is proposed by blocking AP2A2 factor, and allowing the cancer cells to be sensitive to anti-cancer drugs. The effect of AP2A2 on breast cancer was first understood via gene analysis from cBioPortal. AP2A2 was then modeled using RaptorX and its structure was validated from Ramachandran plots. Using all ligands from MolPort database, molecular docking was performed against AP2A2, from which the top three best docked ligands were studied for toxicity in humans using Protox-II. Once the ligands passed these tests, the best complexes were simulated at 200ns in Desmond Maestro, to comprehend their stabilities, followed by the computations of free energies of binding via Molecular mechanics- Generalized Born Solvent Accessibility method (MM-GBSA). The results showed that molecules MolPort-005-945-556 (sachharolipids), MolPort-001-741-124 (flavonoids), and MolPort-005-944-667 (lignan glycosides) with AP2A2 passed toxicity evaluation and belonged to toxicity classes 6, 5, and 5, respectively, with good docking energies. 200 ns simulations revealed stable complexes with slight conformational changes. Stability of ligands was confirmed via snapshots at every 20 ns of the trajectory. Radial distribution of these molecules against the protein revealed very slight deviation from binding pocket. Additionally, the free binding energies for these complexes were found to be - 54.93 ± 12.982 kcal/mol, - 44.39 ± 14.393 kcal/mol, and - 66.51 ± 13.522 kcal/mol, respectively. A preliminary computational validation of the inability of AP2A2 to bind to DLEC1 in the presence of ligands offers beneficial insights into the potential of these ligands. Therefore, this study sheds light on the potential natural molecules that could stably block AP2A2 with least deviation and act in synergy to aid anti-cancer drugs work on breast cancer cells.
Insights
This study identifies natural molecules that block the AP2A2 protein, a key factor in breast cancer development. These molecules enhance the effectiveness of anti-cancer drugs by making cancer cells more sensitive to them.
Area of Science:
- Biochemistry
- Computational Biology
- Pharmacology
Background:
- Transcription factor AP2A2 (activator protein-2 alpha-2) influences DLEC1 gene expression, a tumor suppressor implicated in breast cancer.
- Mutations in DLEC1 are linked to breast cancer, making AP2A2 a potential therapeutic target.
Purpose of the Study:
- To propose a synergistic approach for combating breast cancer by blocking AP2A2.
- To identify natural molecules that can inhibit AP2A2 and enhance anti-cancer drug efficacy.
Main Methods:
- Gene analysis using cBioPortal to understand AP2A2's role in breast cancer.
- Protein structure modeling of AP2A2 using RaptorX and validation.
- Molecular docking of ligands from MolPort against AP2A2.
- Toxicity assessment of docked ligands using Protox-II.
- Molecular dynamics simulations (200 ns) using Desmond Maestro.
- Binding free energy calculations using MM-GBSA.
Main Results:
- Three molecules (sachharolipids, flavonoids, lignan glycosides) showed good docking energies and passed toxicity evaluations.
- Simulations confirmed stable complexes with minimal conformational changes and ligand deviation from the binding pocket.
- Calculated binding free energies ranged from -44.39 ± 14.393 kcal/mol to -66.51 ± 13.522 kcal/mol.
Conclusions:
- The identified natural molecules demonstrate potential for stably blocking AP2A2.
- These molecules could act synergistically with anti-cancer drugs, enhancing their efficacy against breast cancer cells.
- This study provides computational validation for targeting AP2A2 with natural compounds in breast cancer therapy.
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