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Targeting Caspase 8: Using Structural and Ligand-Based Approaches to Identify Potential Leads for the Treatment of Multi-Neurodegenerative Diseases

Caspase 8 is a central player in the apoptotic cell death pathway and is also essential for cytokine processing. The critical role of this protease in cell death pathways has generated research interest because its activation has also been linked with neural cell death. Thus, blocking the activity o...

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Autores principales: Ahmad, Khurshid, Balaramnavar, Vishal M., Chaturvedi, Navaneet, Khan, Saif, Haque, Shafiul, Lee, Yong-Ho, Choi, Inho
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539313/
https://www.ncbi.nlm.nih.gov/pubmed/31083628
http://dx.doi.org/10.3390/molecules24091827
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author Ahmad, Khurshid
Balaramnavar, Vishal M.
Chaturvedi, Navaneet
Khan, Saif
Haque, Shafiul
Lee, Yong-Ho
Choi, Inho
author_facet Ahmad, Khurshid
Balaramnavar, Vishal M.
Chaturvedi, Navaneet
Khan, Saif
Haque, Shafiul
Lee, Yong-Ho
Choi, Inho
author_sort Ahmad, Khurshid
collection PubMed
description Caspase 8 is a central player in the apoptotic cell death pathway and is also essential for cytokine processing. The critical role of this protease in cell death pathways has generated research interest because its activation has also been linked with neural cell death. Thus, blocking the activity of caspase 8 is considered a potential therapy for neurodegenerative diseases. To extend the repertoire of caspase 8 inhibitors, we employed several computational approaches to identify potential caspase 8 inhibitors. Based on the structural information of reported inhibitors, we designed several individual and consensus pharmacophore models and then screened the ZINC database, which contains 105,480 compounds. Screening generated 5332 candidates, but after applying stringent criteria only two candidate compounds, ZINC19370490 and ZINC04534268, were evaluated by molecular dynamics simulations and subjected to Molecular Mechanics/Poisson Boltzmann Surface Area (MM-PBSA) analysis. These compounds were stable throughout simulations and interacted with targeted protein by forming hydrogen and van der Waal bonds. MM-PBSA analysis showed that these compounds were comparable or better than reported caspase 8 inhibitors. Furthermore, their physical properties were found to be acceptable, and they are non-toxic according to the ADMET online server. We suggest that the inhibitory efficacies of ZINC19370490 and ZINC04534268 be subjected to experimental validation.
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spelling pubmed-65393132019-05-31 Targeting Caspase 8: Using Structural and Ligand-Based Approaches to Identify Potential Leads for the Treatment of Multi-Neurodegenerative Diseases Ahmad, Khurshid Balaramnavar, Vishal M. Chaturvedi, Navaneet Khan, Saif Haque, Shafiul Lee, Yong-Ho Choi, Inho Molecules Article Caspase 8 is a central player in the apoptotic cell death pathway and is also essential for cytokine processing. The critical role of this protease in cell death pathways has generated research interest because its activation has also been linked with neural cell death. Thus, blocking the activity of caspase 8 is considered a potential therapy for neurodegenerative diseases. To extend the repertoire of caspase 8 inhibitors, we employed several computational approaches to identify potential caspase 8 inhibitors. Based on the structural information of reported inhibitors, we designed several individual and consensus pharmacophore models and then screened the ZINC database, which contains 105,480 compounds. Screening generated 5332 candidates, but after applying stringent criteria only two candidate compounds, ZINC19370490 and ZINC04534268, were evaluated by molecular dynamics simulations and subjected to Molecular Mechanics/Poisson Boltzmann Surface Area (MM-PBSA) analysis. These compounds were stable throughout simulations and interacted with targeted protein by forming hydrogen and van der Waal bonds. MM-PBSA analysis showed that these compounds were comparable or better than reported caspase 8 inhibitors. Furthermore, their physical properties were found to be acceptable, and they are non-toxic according to the ADMET online server. We suggest that the inhibitory efficacies of ZINC19370490 and ZINC04534268 be subjected to experimental validation. MDPI 2019-05-12 /pmc/articles/PMC6539313/ /pubmed/31083628 http://dx.doi.org/10.3390/molecules24091827 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ahmad, Khurshid
Balaramnavar, Vishal M.
Chaturvedi, Navaneet
Khan, Saif
Haque, Shafiul
Lee, Yong-Ho
Choi, Inho
Targeting Caspase 8: Using Structural and Ligand-Based Approaches to Identify Potential Leads for the Treatment of Multi-Neurodegenerative Diseases
title Targeting Caspase 8: Using Structural and Ligand-Based Approaches to Identify Potential Leads for the Treatment of Multi-Neurodegenerative Diseases
title_full Targeting Caspase 8: Using Structural and Ligand-Based Approaches to Identify Potential Leads for the Treatment of Multi-Neurodegenerative Diseases
title_fullStr Targeting Caspase 8: Using Structural and Ligand-Based Approaches to Identify Potential Leads for the Treatment of Multi-Neurodegenerative Diseases
title_full_unstemmed Targeting Caspase 8: Using Structural and Ligand-Based Approaches to Identify Potential Leads for the Treatment of Multi-Neurodegenerative Diseases
title_short Targeting Caspase 8: Using Structural and Ligand-Based Approaches to Identify Potential Leads for the Treatment of Multi-Neurodegenerative Diseases
title_sort targeting caspase 8: using structural and ligand-based approaches to identify potential leads for the treatment of multi-neurodegenerative diseases
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539313/
https://www.ncbi.nlm.nih.gov/pubmed/31083628
http://dx.doi.org/10.3390/molecules24091827
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