Exploring the Potential of Approved Drugs for Triple-negative Breast Cancer Treatment by Targeting Casein Kinase 2: Insights From Computational Studies
Tagyedeen H. Shoaib,Walaa Ibraheem, Mohammed Abdelrahman, Wadah Osman, Asmaa E. Sherif, Ahmed Ashour, Sabrin R. M. Ibrahim, Kholoud F. Ghazawi, Samar F. Miski, Sara A. Almadani, Duaa Fahad ALsiyud, Gamal A. Mohamed,Abdulrahim A. Alzain
Abstract
Triple-negative breast cancer (TNBC) is an aggressive malignancy that requires effective targeted drug therapy. In this study, we employed in silico methods to evaluate the efficacy of seven approved drugs against human ck2 alpha kinase, a significant modulator of TNBC metastasis and invasiveness. Molecular docking revealed that the co-crystallized reference inhibitor 108600 achieved a docking score of (-7.390 kcal/mol). Notably, among the seven approved drugs tested, sunitinib, bazedoxifene, and etravirine exhibited superior docking scores compared to the reference inhibitor. Specifically, their respective docking scores were -10.401, -7.937, and -7.743 kcal/mol. Further analysis using MM/GBSA demonstrated that these three top-ranked drugs possessed better binding energies than the reference ligand. Subsequent molecular dynamics simulations identified etravirine, an FDA-approved antiviral drug, as the only repurposed drug that demonstrated a stable and reliable binding mode with the human ck2 alpha protein, based on various analysis measures including RMSD, RMSF, and radius of gyration. Principal component analysis indicated that etravirine exhibited comparable stability of motion as a complex with human ck2 alpha protein, similar to the co-crystallized inhibitor. Additionally, Density functional theory (DFT) calculations were performed on a complex of etravirine and a representative gold atom positioned at different sites relative to the heteroatoms of etravirine.
Introduction
In 2020, female breast cancer emerged as the most commonly diagnosed cancer, with an estimated 2.3 million new cases worldwide [1]. Notably, it also represents the leading cause of cancer incidence and mortality among women. Among the various types of breast cancer, triple-negative breast cancer (TNBC) accounts for approximately 10% to 15% of all diagnosed cases [2]. TNBC is characterized by the absence of estrogen receptor (ER), progesterone receptors (PR), and human epidermal growth factor receptors (HER2) expression [3–6]. Targeted therapeutic strategies have been successfully employed for the treatment of ER-positive and HER2-positive subtypes of breast cancer [7]. However, TNBCs do not respond to targeted therapies and are typically treated with nonselective chemotherapy drugs. TNBCs exhibit more aggressive clinical manifestations, higher rates of relapse, and the molecular mechanisms underlying relapse are not yet fully understood [8,9]. Consequently, TNBCs represent the most malignant form of breast cancer, necessitating the urgent discovery of novel targeted therapies [10,11].
Materials and methods
Computational resources
The in silico studies were performed using Maestro v12.8, a molecular modelling software developed by Schrödinger Inc. Maestro offers a range of tools for various molecular modelling tasks, including protein structure prediction, ligand docking, molecular dynamics simulations, and analysis of simulation results. For molecular dynamics (MD) simulations, GROMACS 2022.2 was employed. GROMACS is an open-source simulation software widely utilized in computational chemistry for studying biomolecules through MD simulations. It is known for its efficiency, high performance, and user-friendly interface. DFT calculations were conducted using Gaussian 16 software. Gaussian 16 is a popular software extensively used in computational chemistry for performing diverse electronic structure calculations, including DFT. It provides a comprehensive set of tools for the interpretation, evaluation, and visualization of the results obtained from these calculations.
Results
Molecular docking and MM/GBSA calculations
The docking scores and binding interactions of the selected drugs with human ck2 alpha kinase were analysed and compared to the co-crystallized ligand. The co-crystallized reference ligand, known as inhibitor 108600, is a novel multi-kinase inhibitor designed to target TNBC growth. Experimental studies have shown that this inhibitor reduces the viability of TNBC stem cells, induces unfavourable conformational changes in the human ck2 alpha enzyme, triggers apoptosis of TNBC stem cells, inhibits the growth of chemotherapy-resistant stem cells, and demonstrates efficacy in inhibiting TNBC growth both as a standalone treatment and in combination with other chemotherapeutic agents. Importantly, it synergizes with paclitaxel, thereby inhibiting metastatic TNBC in vivo [51].
Discussion
DFT calculations
The drug etravirine, which has been approved for use by the FDA, was subjected to DFT calculations after demonstrating a relatively better docking score than the co-crystallized ligand, along with a stable and reliable MD profile. The purpose of this quantum mechanical study was to evaluate the interaction energy between etravirine and a gold atom, which could assist in the design of gold nanoparticle carriers for this drug in the treatment of TNBC. Hence, Frequency and optimization were initially conducted on a single gold atom as a representative of a gold nanoparticle carrier and positioned in front of the various heteroatoms present in etravirine. After that, the electronic energy and zero-point energy of both the gold atom and etravirine were calculated. Next, both entities were brought into proximity at an interaction distance of 2.8 angstroms. The energy of the resulting complex was determined and penalized by the sum of the energies of the individual monomers. The results, presented in Fig 8, indicate that the lowest energy (-6.6 kcal/mol) complex was observed when the gold atom was placed in front of nitrogen number 8. Generally, the placement of the gold atom at different sites around the heteroatoms yielded stable complexes with low energy, suggesting their potential as guides for experimental gold nanoparticle carriers for etravirine.
Conclusion
The primary objective of this research study was to identify approved drugs that can effectively combat TNBC using computational techniques such as molecular docking, MD, and DFT calculations. Through molecular docking and MM/GBSA analysis, three drugs (sunitinib, bazedoxifene, and etravirine) were identified as having a higher binding affinity towards the ck2 alpha protein compared to the co-crystallized inhibitor. Further refinement of the three drugs revealed that only etravirine, an antiviral medication, exhibited a more stable and reliable binding mode with the protein than the reference ligand (inhibitor 108600). Etravirine is known to have a safe clinical profile. DFT quantum mechanical calculations were conducted to determine the interaction energy between etravirine and a representative gold atom, resulting in a stable interaction energy. This finding suggests a potential formulation of the drug as a gold nanoparticle for intravenous delivery in TNBC patients. The in silico results provided in this study indicate that etravirine could be repurposed in TNBC treatment regimens after further laboratory and consequent clinical assessments and trials.
Citation: Shoaib TH, Ibraheem W, Abdelrahman M, Osman W, Sherif AE, Ashour A, et al. (2023) Exploring the potential of approved drugs for triple-negative breast cancer treatment by targeting casein kinase 2: Insights from computational studies. PLoS ONE 18(8): e0289887. https://doi.org/10.1371/journal.pone.0289887
Editor: Wagdy Mohamed Eldehna, kafrelsheikh University, EGYPT
Received: May 4, 2023; Accepted: July 27, 2023; Published: August 14, 2023
Copyright: © 2023 Shoaib et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This study is supported via funding from Prince Sattam bin Abdulaziz University. Project number (PSAU/2023/R/1444). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0289887
