Structure-Based Multi-Targeted Molecular Docking and Dynamic Simulation of Soybean-Derived Isoflavone Genistin as a Potential Breast Cancer Signaling Proteins Inhibitor

Abstract

Globally, breast cancer (BC), the second-biggest cause of cancer death, occurs due to unregulated cell proliferation leading to metastasis to other parts of the human organ. Recently, the exploration of naturally derived anticancer agents has become popular due to their fewer adverse effects. Among the natural products, soybean is a very well-known legume that contains important bioactive compounds such as diadazine, glycetin, genistein, and genistin. Therefore, keeping its therapeutic potential in mind, multi-targeted molecular docking and simulation studies were conducted to explore the potential role of soybean-derived isoflavone genistin against several breast cancer-signaling proteins (ER-alpha, ER-Beta, collapsin response mediator protein 2, CA 15-3, human epidermal growth factor receptor 2). A comparative study of the genistin-protein docked complex was explored to investigate its potential role in BC. The molecular binding energy (∆G) of the docked complex was calculated along with ADMET properties. The molecular docking score of genistin with ubiquitin-like protein activation complex-a type of Cancer Antigen (CA) 15.3 (PDB ID-2NVU, 5T6P, and 1YX8) showed the highest binding energy, ranging from -9.5 to -7.0 Kcal/mol, respectively. Furthermore, the highest docking scores of the complex were additionally put through molecular dynamics (MD) simulation analysis. MD simulations of the selected complex were performed at 100 ns to study the stability of the genistin-ubiquitin-like protein CA 15.3 complex, which appeared to be quite stable. Additionally, the ADMET study demonstrated that genistin complies with all drug-likeness standards, including Lipinski, Egan, Veber, Ghose, and Muegge. Therefore, based on the results, genistin can be considered as one of the potential drugs for the management and treatment of BC. In addition, the obtained results suggest that genistin could pave the way for new drug discovery to manage breast cancer and has potential in the development of nutraceuticals.

Keywords: breast cancer-signaling proteins; cancer; cancer antigen; genistin; isoflavone compounds; molecular dynamics.

Figure 1

Genistin chemical structure (center). The human proteins associated with the development of breast cancer are Collapsin response mediator protein 2 (PDB ID-5LXX), Breast cancer antigen 15.3 (Ca 15.3) (PDB ID-1Y8X), ubiquitin-like protein activation complex (PDB ID-2NVU), human epidermal growth factor receptor 2 (PDB ID-7PCD), ER-α (PDB ID-6CHZ), ER-β (PDB ID-5TOA), glycoprotein Mucin 1 (MUC1) (PDB ID-5T6P) were individually docked with genistin.

Figure 2

Significant molecular bonding of genistin with (A) ER-β (PDB ID-5TOA) and (C) Collapsin response mediator protein 2 (PDB ID-5LXX) receptors. The enlarged image illustrates the acceptor amino acid residues and hydrogen bond donors in the junction cavity. The 2D images of (B) ER-β and (D) CRMP2 show genistin interacting with binding pocket residues as a protein inhibitor.

Figure 3

Significant molecular bonding of genistin with (A) breast cancer antigen 15.3 (PDB ID-1Y8X), (C) ubiquitin-like protein activation complex (PDB ID-2NVU) and (E) glycoprotein Mucin 1 (PDB ID-5T6P). The enlarged image illustrates the acceptor amino acid residues and hydrogen bonds donor in the junction cavity. The 2D image (B) breast cancer antigen 15.3, (D) ubiquitin-like protein activation complex, and (F) glycoprotein Mucin 1 shows the genistin interacting with binding pocket residues as a protein inhibitor.

Figure 4

Significant interaction of genistin with (A) ER alpha (PDB ID-6CHZ) and (C) human epidermal growth factor receptor 2 (PDB ID-7PCD) The enlarged image illustrates the acceptor amino acid residues and hydrogen bonds donor in the junction cavity. The 2D image (B) ER alpha and (D) HER2 shows the genistin interacting with binding pocket residues as a protein inhibitor.

Figure 5

The root mean square deviation (RMSD) as a simulation time for genistin/breast cancer antigen 15.3 complex (PDB ID-1Y8X) as determined by molecular dynamics simulation.

Figure 6

(A) The root mean square (RMS) fluctuation of the genistin/breast cancer antigen 15.3 complex. (B) The radius of gyration (Rg) for genistin/breast cancer antigen 15.3 complex (PDB ID-1Y8X).