Virtual screening and molecular dynamics simulations identify repurposed drugs as potent inhibitors of Histone deacetylase 1: Implication in cancer therapeutics
Mohammed Alrouji, Sabina Yasmin, Mohammed S. Alshammari, Fahad A. Alhumaydhi, Sharaf E. Sharaf, Moyad Shahwan, Anas Shamsi
Abstract
Epigenetic processes are the critical events in carcinogenesis. Histone modification plays a crucial role in gene expression regulation, where histone deacetylases (HDACs) are key players in epigenetic processes. Inhibiting HDACs has shown promise in modern cancer therapy. However, the non-selective nature and drug resistance of most HDAC inhibitors (HDACIs) limits their clinical use. This limitation prompts a search for isoform-selective and more effective inhibitors.
Introduction
Cancer is a complex and multifactorial disease that remains one of the leading causes of mortality worldwide [1]. The cancer incidence rises steadily across modern populations. Even though significant progress has been made in studying the molecular mechanisms of cancer, the management of this disease remains a substantial challenge [2]. One of the distinctive features of cancer is the violation of epigenetic processes [3]. These processes influence the patterns of gene expression without changing the DNA sequence of the gene in question [4].
Materials and method
2.1. Computational resources
The computations were performed using an HP Z840 server, and the power supply to the server was kept constant for the study. Molecular docking screening was performed by using several programs like MGL AutoDock [21] and InstaDock [22]. All structural analysis and visualization of the molecular complexes were done using PyMOL [23] and Discovery Studio Visualizer [24]. Concerning the identified sources of data, different web-based resources and databases were used for data collection and analysis. The RCSB Protein Data Bank (PDB) was exploited for structural details of the target HDAC1 [25, 26].
Results
3.1. Molecular docking-based virtual screening
Molecular docking screening was performed to find the compounds that have high binding affinity to HDAC1. This was done from a list of repurposed drugs obtained from the DrugBank database of approved drugs. The screening process produced affinity scores and most likely docked poses for each compound in the library. This made it possible to get candidates with high binding affinity to HDAC1. After the screening process, compounds were further eliminated according to their ability to bind to HDAC1.
Discussion
HDAC1 belongs to Class I of HDACs and plays a critical role in gene regulation and is directly associated with carcinogenesis and neurodegenerative diseases [41]. In this study, Alectinib, an ALK inhibitor previously approved by FDA, is considered as a potential repurposed drug targeting HDAC1. The findings demonstrate the ability of Alectinib to serve as a potential HDAC1 repurposed inhibitor through virtual screening, molecular docking, MD simulations, and MM-PBSA binding free energy estimations. The results reveal that Alectinib interacts more potently with HDAC1 than the reference inhibitor Pyroxamide based on the docking scores and stable MD simulation.
Conclusion
Targeting HDAC1 through repurposed drugs is a promising strategy for therapeutic development in modern drug discovery against cancer and neurodegeneration. This study has given a new perspective on the relationship between HDAC1 and Alectinib as its repurposed inhibitor molecule. The virtual screening, molecular dynamics, and conformational dynamics studies such as RMSD, RMSF, Rg, SASA, hydrogen bonding, secondary structure, and PCA confirmed that Alectinib could be repurposed for targeting HDAC1. In particular, the interaction between Alectinib and HDAC1 involves the formation of strong hydrogen bonds that ensure the stability of the complex.
Citation: Alrouji M, Yasmin S, Alshammari MS, Alhumaydhi FA, Sharaf SE, Shahwan M, et al. (2025) Virtual screening and molecular dynamics simulations identify repurposed drugs as potent inhibitors of Histone deacetylase 1: Implication in cancer therapeutics. PLoS ONE 20(1): e0316343. https://doi.org/10.1371/journal.pone.0316343
Editor: Martiniano Bello Ramírez, Instituto Politecnico Nacional, MEXICO
Received: July 29, 2024; Accepted: December 10, 2024; Published: January 3, 2025
Copyright: © 2025 Alrouji 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: The authors extend their appreciation to the Deanship of Research and Graduate studies at King Khalid University for funding this work through Large Research project under grant number (RGP .2 /244/45). MA would like to thank the Deanship of Scientific Research at Shaqra University for supporting this work. AS is thankful to Ajman University, UAE for supporting this publication. We confirm that the funders had no role in the study. The amended statement reads as follows.
Competing interests: The authors have declared that no competing interests exist.
