Unveiling Cathepsin B inhibition with repurposed drugs for anticancer and anti-Alzheimer’s drug discovery
Mohammed Alrouji, Sabina Yasmin, Mohammed S. Alshammari, Fahad A. Alhumaydhi, Sharaf E. Sharaf, Moyad Shahwan, Anas Shamsi
Abstract
Alzheimer’s disease (AD) is characterized by the aggregation of amyloid β (Aβ) peptides and the formation of plaques in the brain, primarily derived from the proteolytic degradation of amyloid precursor protein (APP). Cathepsin B (CatB) is a cysteine protease that plays a pivotal role in this process, making it a potential target for the development of anti-Alzheimer’s therapies. Apart from AD, CatB is implicated in various physiological and pathological processes, including cancer.
Introduction
Alzheimer’s disease (AD) remains a pressing global health challenge that impacts over 50 million individuals globally [1, 2]. It is characterized by a gradual decline in cognitive function and neuropathological changes, including the formation of amyloid β (Aβ) aggregates and plaques in the brain [3]. The proteolytic cleavage of amyloid precursor protein (APP) is a pivotal step in the generation of Aβ, and dysregulation of this process is considered a central pathological hallmark of AD [4].
Materials and method
2.1. Computer environment and web resources
Molecular docking-based virtual screening and visualization were conducted using multiple computational software, including MGL AutoDock tools [25], PyMOL [26], InstaDock [27], and Discovery Studio Visualizer [28]. These tools were used to explore ligand-receptor interactions and provide three-dimensional structural representations. Various bioinformatics resources such as UniProt [29], DrugBank [30], and Pass Online [31] were exploited for data retrieval and analysis.
Results and discussion
3.1. Molecular docking-based virtual screening
Molecular docking-based virtual screening is a powerful tool in drug discovery that allows rapidly screen large chemical libraries and prioritize the most promising candidates for the drug discovery process [44]. To identify high-affinity binding partners for CatB, a molecular docking-based virtual screening was conducted on a library comprising 3500 molecules sourced from the DrugBank database. Utilizing InstaDock, each molecule underwent molecular docking screening, which generates affinity scores and docked poses. The results of the docking protocol validation confirmed its ability to accurately replicate the binding pose of a dipeptidyl nitrile inhibitor from the CatB co-crystal structure (PDB ID: 1GMY).
Conclusion
CatB plays a critical role in AD development and cancer progression, making it a viable therapeutic target. This study identified Lurasidone and Paliperidone as effective CatB modulators through molecular docking and MD simulations. Both compounds demonstrated high binding affinities to functionally relevant residues in the CatB catalytic pocket, supporting their selectivity and therapeutic potential. Structural stability observed during MD simulations, along with insights from PCA and FEL analyses, further validated their potential as CatB inhibitors.
Citation: Alrouji M, Yasmin S, Alshammari MS, Alhumaydhi FA, Sharaf SE, Shahwan M, et al. (2024) Unveiling Cathepsin B inhibition with repurposed drugs for anticancer and anti-Alzheimer’s drug discovery. PLoS ONE 19(12): e0316010. https://doi.org/10.1371/journal.pone.0316010
Editor: Ahmed A. Al-Karmalawy, University of Mashreq, IRAQ
Received: March 5, 2024; Accepted: December 4, 2024; Published: December 19, 2024
Copyright: © 2024 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 the data is present in the manuscript.
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. A.S. is thankful to Ajman University, UAE, for supporting this publication. 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.
