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.

In Silico Computational Studies of Bioactive Secondary Metabolites from Wedelia trilobata against Anti-Apoptotic B-Cell Lymphoma-2 (Bcl-2) Protein Associated with Cancer Cell Survival and Resistance

“…The molecular docking experiment was executed using AutoDock Vina software integrated in the PyRx 0.8 tool, based on the Lamarckian Genetic Algorithm, to study the ligand interaction with the active site residues of Bcl-2 structure [ 31 , 32 ]. The cubical grid box dimension for the XYZ coordinates was fixed at 60 × 60 × 60 Å with 0.375 Å around the active binding sites of the 2W3L protein.…”

Phyto‐therapeutic potential of Withania somnifera: Molecular mechanism and health implications

“…W. somnifera slowed the regulation of development of malignant cells in the lungs, breast, colon, cervical, prostate, and central nervous system cell lines (Figures 1 and 2; Table 3) (Widodo et al, 2007;Wadhwa et al, 2013;Choi & Kim, 2015;Gowtham et al, 2022). Compared to the well-known anticancer medication doxorubicin, Withaferin A greatly slowed the development of breast and colon tumors (Fong, 2012). The inducible or constitutive modes of suppression that led to an increase in apoptosis by introducing Bim-S and Mim-L in MCF-7 and MDAMB-231 type cells, a reduction in the invasion, and an increase in osteoclastogenesis may be involved in blocking NF activation sites (Sivasankarapillai et al 2020).…”

“…The traditionally reputed plan showed great promise in experiments pertaining to cancer research, many a times using cell lines. W. somnifera slowed the regulation of development of malignant cells in the lungs, breast, colon, cervical, prostate, and central nervous system cell lines (Figures 1 and 2; Table 3) (Widodo et al, 2007; Wadhwa et al, 2013; Choi & Kim, 2015; Gowtham et al, 2022). Compared to the well‐known anticancer medication doxorubicin, Withaferin A greatly slowed the development of breast and colon tumors (Fong, 2012).…”

Secondary metabolites of Trichoderma spp. as EGFR tyrosine kinase inhibitors: Evaluation of anticancer efficacy through computational approach

“…are fungi with the extraordinary ability to produce abundant secondary metabolites with great therapeutic potential [ 14 ]. It has been well documented that in silico evaluation of the secondary metabolites through molecular docking, molecular dynamic (MD) simulation and pharmacokinetic properties will have a substantial role in the detection of new metabolites of importance [ 15 – 17 ]. Based on the above facts, the main focus of the present study was to identify the new potential compounds from Trichoderma spp.…”