Abstract
Cathepsin B is a cysteine protease that belongs to the papain superfamily. Malfunctions related to cathepsin B can lead to inflammation and cancer. Via an integrated in silico approach, this study is aimed to identify novel Michael acceptors-type compounds that can irreversibly inhibit cathepsin B enzyme via covalent bond formation with the active site cysteine residue. Here, we report the first account of covalent docking approach incorporated into a hybrid ligand/structure-based virtual screening to estimate the binding affinities of various compounds from chemical databases against the cathepsin B protein. For validation, compounds with experimentally determined anti-cathepsin B activity from PubChem bioassay database were also screened and covalently docked to the enzyme target. Interestingly, four novel compounds exhibited better covalent binding affinity when compared against the experimentally determined prototypes. Molecular dynamics simulations were performed to ensure the stability of the docked complexes and to allow further analysis on the MD average structures. Perresidue interaction decomposition analysis was carried out to provide deeper insight into the interaction themes of discovered hits with the active site residues. It is found that polar and hydrophobic interactions contributed the most towards drug binding.
The hybrid computational methods applied in this study should serve as a powerful tool in the drug design and development process.
Keywords: Cathepsin B, covalent docking, Michael acceptors, molecular dynamics, virtual screening.
Combinatorial Chemistry & High Throughput Screening
Title:In Silico Identification of Irreversible Cathepsin B Inhibitors as Anti- Cancer Agents: Virtual Screening, Covalent Docking Analysis and Molecular Dynamics Simulations
Volume: 18 Issue: 4
Author(s): Mbatha Sbongile and Mahmoud E.S. Soliman
Affiliation:
Keywords: Cathepsin B, covalent docking, Michael acceptors, molecular dynamics, virtual screening.
Abstract: Cathepsin B is a cysteine protease that belongs to the papain superfamily. Malfunctions related to cathepsin B can lead to inflammation and cancer. Via an integrated in silico approach, this study is aimed to identify novel Michael acceptors-type compounds that can irreversibly inhibit cathepsin B enzyme via covalent bond formation with the active site cysteine residue. Here, we report the first account of covalent docking approach incorporated into a hybrid ligand/structure-based virtual screening to estimate the binding affinities of various compounds from chemical databases against the cathepsin B protein. For validation, compounds with experimentally determined anti-cathepsin B activity from PubChem bioassay database were also screened and covalently docked to the enzyme target. Interestingly, four novel compounds exhibited better covalent binding affinity when compared against the experimentally determined prototypes. Molecular dynamics simulations were performed to ensure the stability of the docked complexes and to allow further analysis on the MD average structures. Perresidue interaction decomposition analysis was carried out to provide deeper insight into the interaction themes of discovered hits with the active site residues. It is found that polar and hydrophobic interactions contributed the most towards drug binding.
The hybrid computational methods applied in this study should serve as a powerful tool in the drug design and development process.
Export Options
About this article
Cite this article as:
Sbongile Mbatha and Soliman E.S. Mahmoud, In Silico Identification of Irreversible Cathepsin B Inhibitors as Anti- Cancer Agents: Virtual Screening, Covalent Docking Analysis and Molecular Dynamics Simulations, Combinatorial Chemistry & High Throughput Screening 2015; 18 (4) . https://dx.doi.org/10.2174/1386207318666150305154621
DOI https://dx.doi.org/10.2174/1386207318666150305154621 |
Print ISSN 1386-2073 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5402 |
Call for Papers in Thematic Issues
Artificial Intelligence Methods for Biomedical, Biochemical and Bioinformatics Problems
Recently, a large number of technologies based on artificial intelligence have been developed and applied to solve a diverse range of problems in the areas of biomedical, biochemical and bioinformatics problems. By utilizing powerful computing resources and massive amounts of data, methods based on artificial intelligence can significantly improve the ...read more
Eco-friendly Agents for Biological Control of Pathogenic Diseases
The discovery of an alternative biological approach to disease management includes work on medicinal products derived from natural sources as a starting point for the development of eco-friendly agents for these diseases and the injuries they cause, as well as reducing human contact with hazardous chemicals and their residues. We ...read more
Emerging trends in diseases mechanisms, noble drug targets and therapeutic strategies: focus on immunological and inflammatory disorders
Recently infectious and inflammatory diseases have been a key concern worldwide due to tremendous morbidity and mortality world Wide. Recent, nCOVID-9 pandemic is a good example for the emerging infectious disease outbreak. The world is facing many emerging and re-emerging diseases out breaks at present however, there is huge lack ...read more
Exploring Spectral Graph Theory in Combinatorial Chemistry
Scope of the Thematic Issue: Combinatorial chemistry involves the synthesis and analysis of a large number of diverse compounds simultaneously. Traditional methods rely on brute force experimentation, which can be time-consuming and resource-intensive. Spectral Graph Theory, a branch of mathematics dealing with the properties of graphs in relation to the ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Glaucoma: Validated and Facile In Vivo Experimental Models of a Chronic Neurodegenerative Disease for Drug Development
Current Medicinal Chemistry - Central Nervous System Agents Current Overview of Inorganic Nanoparticles for the Treatment of Central Nervous System (CNS) Diseases
Current Nanomaterials Resveratrol Protects β Amyloid-Induced Oxidative Damage and Memory Associated Proteins in H19-7 Hippocampal Neuronal Cells
Current Alzheimer Research Defective HIF Signaling Pathway and Brain Response to Hypoxia in Neurodegenerative Diseases: Not an “Iffy” Question!
Current Pharmaceutical Design Genomic and Pharmacogenomic Biomarkers of Parkinson’s Disease
Current Drug Metabolism Patent Selections:
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Inflammation and Age-Related Iron Accumulation in F344 Rats
Current Aging Science Oxidative Stress and Antioxidant Potential of One Hundred Medicinal Plants
Current Topics in Medicinal Chemistry Patent Selections:
Recent Patents on Anti-Cancer Drug Discovery Cucurbitacin E, An Experimental Lead Triterpenoid with Anticancer, Immunomodulatory and Novel Effects Against Degenerative Diseases. A Mini-Review
Current Topics in Medicinal Chemistry Endothelium and Oxidative Stress: The Pandora's Box of Cerebral (and Non-Only) Small Vessel Disease?
Current Molecular Medicine Metal-Score as a Potential Non-Invasive Diagnostic Test for Alzheimer’s Disease
Current Alzheimer Research Involvement of Advanced Glycation End-products (AGEs) in Alzheimers Disease
Current Alzheimer Research Neuronal Death in Amyotrophic Lateral Sclerosis (ALS): What Can We Learn from Genetics?
CNS & Neurological Disorders - Drug Targets Neuroprotective Effects of Fisetin in Alzheimer’s and Parkinson’s Diseases: From Chemistry to Medicine
Current Topics in Medicinal Chemistry Endogenous Retroelements in Cellular Senescence and Related Pathogenic Processes: Promising Drug Targets in Age-Related Diseases
Current Drug Targets Protective Substances Against Zinc-Induced Neuronal Death after Ischemia:Carnosine as a Target for Drug of Vascular Type of Dementia
Recent Patents on CNS Drug Discovery (Discontinued) Recent Advances in the Development of Selective CB2 Agonists as Promising Anti-Inflammatory Agents
Current Medicinal Chemistry Fullerenes: From Carbon to Nanomedicine
Mini-Reviews in Medicinal Chemistry Nanoparticle Coated Viral Vectors for Gene Therapy
Current Biotechnology