Phytoconstituents of Withania somnifera unveiled Ashwagandhanolide as a potential drug targeting breast cancer: Investigations through computational, molecular docking and conceptual DFT studies

Abstract

Breast cancer is the second most common malignancy in females worldwide and poses a great challenge that necessitates the identification of novel therapeutic agents from several sources. This research aimed to study the molecular docking and molecular dynamics simulations of four proteins (such as PDB: 6CBZ, 1FDW, 5GWK and 2WTT) with the selected phytochemicals from Withania somnifera to identify the potential inhibitors for breast cancer. The molecular docking result showed that among 44 compounds, two of them, Ashwagandhanolide and Withanolide sulfoxide have the potential to inhibit estrogen receptor alpha (ERα), 17-beta-hydroxysteroid -dehydrogenase type 1 (17β-HSD1), topoisomerase II alpha (TOP2A) and p73 tetramerization domain that are expressed during breast cancer. The molecular dynamics (MD) simulations results suggested that Ashwagandhanolide remained inside the binding cavity of four targeted proteins and contributed favorably towards forming a stable protein-ligand complex throughout the simulation. Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties confirmed that Ashwagandhanolide is hydrophobic and has moderate intestinal permeability, good intestinal absorption, and poor skin permeability. The compound has a relatively low VDss value (-1.652) and can be transported across ABC transporter and good central nervous system (CNS) permeability but did not easily cross the blood-brain barrier (BBB). This compound does not possess any mutagenicity, hepatotoxicity and skin sensitization. Based on the results obtained, the present study highlights the anticancer potential of Ashwagandhanolide, a compound from W. somnifera. Furthermore, in vitro and in vivo studies are necessary to perform before clinical trials to prove the potentiality of Ashwagandhanolide.

Fig 1. Ramachandran plot for the model of the structure of ERα (PDB: 6CBZ) and human 17β-HSD1 (PDB: 1FDW) proteins generated by PROCHECK.

The red color region denotes residues of the protein in the most favored regions; the brown color denotes residues in the additional allowed regions and the yellow indicates residues in the generously allowed regions.

Fig 2. Ramachandran plot for the model of the structure of human TOP2A (PDB: 5GWK) and human p73 tetramerization domain (PDB: 2WTT) proteins generated by PROCHECK.

The red color region denotes residues of the protein in the most favored regions; the brown color denotes residues in the additional allowed regions and the yellow indicates residues in the generously allowed regions.

Fig 3. Z-score for the model of the structure of multiple proteins generated by ProSA web tool.

Fig 4. Interaction of ERα (PDB: 6CBZ) with Ashwagandhanolide and Withanolide sulfoxide.

Three-dimensional (3D) illustration shows the interaction of ligands with ERα structure and two-dimensional (2D) diagram displays the interactions of the ligand with the specific amino acid residues in the active site of the protein.

Fig 5. Interaction of human 17β-HSD1 (PDB: 1FDW) with Ashwagandhanolide and Withanolide Sulfoxide.

Three-dimensional (3D) illustration shows the interaction of ligands with human 17β-HSD1 structure and two-dimensional (2D) diagram displays the interactions of the ligand with the specific amino acid residues in the active site of the protein.

Fig 6. Interaction of human TOP2A (PDB: 5GWK) with Ashwagandhanolide and Withanolide sulfoxide.

Three-dimensional (3D) illustration shows the interaction of ligands with human TOP2A structure and two-dimensional (2D) diagram displays the interactions of the ligand with the specific amino acid residues in the active site of the protein.

Fig 7. Interaction of human p73 tetramerization domain (PDB: 2WTT) with Ashwagandhanolide and Withanolide Sulfoxide.

Three-dimensional (3D) illustration shows the interaction of ligands with human p73 tetramerization domain structure and two-dimensional (2D) diagram displays the interactions of the ligand with the specific amino acid residues in the active site of the protein.

Fig 8. Analysis of RMSD (A), Rg (B), SASA (C) and Hydrogen (D) graphs of TOP2A (PDB: 5GWK) in complex with Ashwagandhanolide (Back color indicating protein alone and Red indicating protein-ligand complex).

Fig 9. Graphical representation of the dual descriptor DD of Ashwangandhanolide.

Top: DD > 0, Bottom: DD < 0.