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
-
Mitochondrial Tolerance to Drugs and Toxic Agents in Ageing and Disease
Current Drug Targets AFM-Based Single Molecule Techniques: Unraveling the Amyloid Pathogenic Species
Current Pharmaceutical Design Solvent-Free Synthesis of 4,5-Dihydropyrano[c]chromene Derivatives Over TiO<sub>2</sub> Nanoparticles as an Economical and Efficient Catalyst
Current Catalysis The Role of Melatonin in Multiple Sclerosis, Huntington's Disease and Cerebral Ischemia
CNS & Neurological Disorders - Drug Targets Recent Advances in Progressive Supranuclear Palsy: A Review
Current Alzheimer Research From Hybrids to New Scaffolds: The Latest Medicinal Chemistry Goals in Multi-target Directed Ligands for Alzheimer’s Disease
Current Neuropharmacology Can Environmentally Relevant Levels of Aluminium Promote the Onset and Progression of Neurodegenerative Diseases?
Current Inorganic Chemistry (Discontinued) Proteomics as Applied to Inherited Metabolic Diseases
Current Proteomics The Ubiquitin-Proteasome System and Proteasome Inhibitors in Central Nervous System Diseases
Cardiovascular & Hematological Disorders-Drug Targets 6-hydroxydopamine Lesion of the Mesolimbic Dopamine System Alters Morphine-Induced Conditioned Reinforcement
Current Psychopharmacology Chondroitin Sulfate, a Major Niche Substance of Neural Stem Cells, and Cell Transplantation Therapy of Neurodegeneration Combined with Niche Modification
Current Stem Cell Research & Therapy Cytokines in Neuroinflammation and Alzheimers Disease
Current Drug Targets Endocannabinoid Receptors in the CNS: Potential Drug Targets for the Prevention and Treatment of Neurologic and Psychiatric Disorders
Current Neuropharmacology Indole Alkaloids and Semisynthetic Indole Derivatives as Multifunctional Scaffolds Aiming the Inhibition of Enzymes Related to Neurodegenerative Diseases – A Focus on Psychotria L. Genus
Current Topics in Medicinal Chemistry Editorial (Hot Topic: Targeting Histone Acetylation for Neuroprotection)
Current Pharmaceutical Design Cannabinoid Receptors and Endocannabinoids: Role in Neuroinflammatory and Neurodegenerative Disorders
CNS & Neurological Disorders - Drug Targets The High Mobility Group A1 (HMGA1) Transcriptome in Cancer and Development
Current Molecular Medicine The Fragile X Family of Disorders: A Model for Autism and Targeted Treatments
Current Pediatric Reviews Emerging and Alternative Therapies For Parkinson Disease: An Updated Review
Current Pharmaceutical Design Human Pluripotent Stem Cells for Modelling Human Liver Diseases and Cell Therapy
Current Gene Therapy