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A Novel Approach to Develop New and Potent Inhibitors for the Simultaneous Inhibition of Protease and Helicase Activities of HCV NS3/4A Protease: A Computational Approach

Infection of hepatitis C (HCV) is a major threat to human health throughout the world. The current therapy program suffers from restricted efficiency and low tolerance, and there is serious demand frr novel medication. NS3/4A protease is observed to be very effective target for the treatment of HCV....

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Autores principales: Riaz, Muhammad, Rehman, Ashfaq Ur, Waqas, Muhammad, Khalid, Asaad, Abdalla, Ashraf N., Mahmood, Arif, Hu, Junjian, Wadood, Abdul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9918934/
https://www.ncbi.nlm.nih.gov/pubmed/36770965
http://dx.doi.org/10.3390/molecules28031300
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author Riaz, Muhammad
Rehman, Ashfaq Ur
Waqas, Muhammad
Khalid, Asaad
Abdalla, Ashraf N.
Mahmood, Arif
Hu, Junjian
Wadood, Abdul
author_facet Riaz, Muhammad
Rehman, Ashfaq Ur
Waqas, Muhammad
Khalid, Asaad
Abdalla, Ashraf N.
Mahmood, Arif
Hu, Junjian
Wadood, Abdul
author_sort Riaz, Muhammad
collection PubMed
description Infection of hepatitis C (HCV) is a major threat to human health throughout the world. The current therapy program suffers from restricted efficiency and low tolerance, and there is serious demand frr novel medication. NS3/4A protease is observed to be very effective target for the treatment of HCV. A data set of the already reported HCV NS3/4A protease inhibitors was first docked into the NS3/4A protease (PDB ID: 4A92A) active sites of both protease and helicase sites for calculating the docking score, binding affinity, binding mode, and solvation energy. Then the data set of these reported inhibitors was used in a computer-based program “RECAP Analyses” implemented in MOE to fragment every molecule in the subset according to simple retrosynthetic analysis rules. The RECAP analysis fragments were then used in another computer-based program “RECAP Synthesis” to randomly recombine and generate synthetically reasonable novel chemical structures. The novel chemical structures thus produced were then docked against HCV NS3/4A. After a thorough validation of all undertaken steps, based on Lipinski’s rule of five, docking score, binding affinity, solvation energy, and Van der Waal’s interactions with HCV NS3/4A, 12 novel chemical structures were identified as inhibitors of HCV NS3/4A. The novel structures thus designed are hoped to play a key role in the development of new effective inhibitors of HCV.
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spelling pubmed-99189342023-02-12 A Novel Approach to Develop New and Potent Inhibitors for the Simultaneous Inhibition of Protease and Helicase Activities of HCV NS3/4A Protease: A Computational Approach Riaz, Muhammad Rehman, Ashfaq Ur Waqas, Muhammad Khalid, Asaad Abdalla, Ashraf N. Mahmood, Arif Hu, Junjian Wadood, Abdul Molecules Article Infection of hepatitis C (HCV) is a major threat to human health throughout the world. The current therapy program suffers from restricted efficiency and low tolerance, and there is serious demand frr novel medication. NS3/4A protease is observed to be very effective target for the treatment of HCV. A data set of the already reported HCV NS3/4A protease inhibitors was first docked into the NS3/4A protease (PDB ID: 4A92A) active sites of both protease and helicase sites for calculating the docking score, binding affinity, binding mode, and solvation energy. Then the data set of these reported inhibitors was used in a computer-based program “RECAP Analyses” implemented in MOE to fragment every molecule in the subset according to simple retrosynthetic analysis rules. The RECAP analysis fragments were then used in another computer-based program “RECAP Synthesis” to randomly recombine and generate synthetically reasonable novel chemical structures. The novel chemical structures thus produced were then docked against HCV NS3/4A. After a thorough validation of all undertaken steps, based on Lipinski’s rule of five, docking score, binding affinity, solvation energy, and Van der Waal’s interactions with HCV NS3/4A, 12 novel chemical structures were identified as inhibitors of HCV NS3/4A. The novel structures thus designed are hoped to play a key role in the development of new effective inhibitors of HCV. MDPI 2023-01-29 /pmc/articles/PMC9918934/ /pubmed/36770965 http://dx.doi.org/10.3390/molecules28031300 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Riaz, Muhammad
Rehman, Ashfaq Ur
Waqas, Muhammad
Khalid, Asaad
Abdalla, Ashraf N.
Mahmood, Arif
Hu, Junjian
Wadood, Abdul
A Novel Approach to Develop New and Potent Inhibitors for the Simultaneous Inhibition of Protease and Helicase Activities of HCV NS3/4A Protease: A Computational Approach
title A Novel Approach to Develop New and Potent Inhibitors for the Simultaneous Inhibition of Protease and Helicase Activities of HCV NS3/4A Protease: A Computational Approach
title_full A Novel Approach to Develop New and Potent Inhibitors for the Simultaneous Inhibition of Protease and Helicase Activities of HCV NS3/4A Protease: A Computational Approach
title_fullStr A Novel Approach to Develop New and Potent Inhibitors for the Simultaneous Inhibition of Protease and Helicase Activities of HCV NS3/4A Protease: A Computational Approach
title_full_unstemmed A Novel Approach to Develop New and Potent Inhibitors for the Simultaneous Inhibition of Protease and Helicase Activities of HCV NS3/4A Protease: A Computational Approach
title_short A Novel Approach to Develop New and Potent Inhibitors for the Simultaneous Inhibition of Protease and Helicase Activities of HCV NS3/4A Protease: A Computational Approach
title_sort novel approach to develop new and potent inhibitors for the simultaneous inhibition of protease and helicase activities of hcv ns3/4a protease: a computational approach
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9918934/
https://www.ncbi.nlm.nih.gov/pubmed/36770965
http://dx.doi.org/10.3390/molecules28031300
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