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Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1): An in Silico Approach

A new Plasmodium falciparum histone deacetylase1 (PfHDAC1) homology model was built based on the highest sequence identity available template human histone deacetylase 2 structure. The generated model was carefully evaluated for stereochemical accuracy, folding correctness and overall structure qual...

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Autores principales: Elbadawi, Mohamed A. Abdallah, Awadalla, Mohamed Khalid Alhaj, Abdel Hamid, Muzamil Mahdi, Mohamed, Magdi Awadalla, Awad, Talal Ahmed
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2015
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346934/
https://www.ncbi.nlm.nih.gov/pubmed/25679451
http://dx.doi.org/10.3390/ijms16023915
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author Elbadawi, Mohamed A. Abdallah
Awadalla, Mohamed Khalid Alhaj
Abdel Hamid, Muzamil Mahdi
Mohamed, Magdi Awadalla
Awad, Talal Ahmed
author_facet Elbadawi, Mohamed A. Abdallah
Awadalla, Mohamed Khalid Alhaj
Abdel Hamid, Muzamil Mahdi
Mohamed, Magdi Awadalla
Awad, Talal Ahmed
author_sort Elbadawi, Mohamed A. Abdallah
collection PubMed
description A new Plasmodium falciparum histone deacetylase1 (PfHDAC1) homology model was built based on the highest sequence identity available template human histone deacetylase 2 structure. The generated model was carefully evaluated for stereochemical accuracy, folding correctness and overall structure quality. All evaluations were acceptable and consistent. Docking a group of hydroxamic acid histone deacetylase inhibitors and valproic acid has shown binding poses that agree well with inhibitor-bound histone deacetylase-solved structural interactions. Docking affinity dG scores were in agreement with available experimental binding affinities. Further, enzyme-ligand complex stability and reliability were investigated by running 5-nanosecond molecular dynamics simulations. Thorough analysis of the simulation trajectories has shown that enzyme-ligand complexes were stable during the simulation period. Interestingly, the calculated theoretical binding energies of the docked hydroxamic acid inhibitors have shown that the model can discriminate between strong and weaker inhibitors and agrees well with the experimental affinities reported in the literature. The model and the docking methodology can be used in screening virtual libraries for PfHDAC1 inhibitors, since the docking scores have ranked ligands in accordance with experimental binding affinities. Valproic acid calculated theoretical binding energy suggests that it may inhibit PfHDAC1.
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spelling pubmed-43469342015-04-03 Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1): An in Silico Approach Elbadawi, Mohamed A. Abdallah Awadalla, Mohamed Khalid Alhaj Abdel Hamid, Muzamil Mahdi Mohamed, Magdi Awadalla Awad, Talal Ahmed Int J Mol Sci Article A new Plasmodium falciparum histone deacetylase1 (PfHDAC1) homology model was built based on the highest sequence identity available template human histone deacetylase 2 structure. The generated model was carefully evaluated for stereochemical accuracy, folding correctness and overall structure quality. All evaluations were acceptable and consistent. Docking a group of hydroxamic acid histone deacetylase inhibitors and valproic acid has shown binding poses that agree well with inhibitor-bound histone deacetylase-solved structural interactions. Docking affinity dG scores were in agreement with available experimental binding affinities. Further, enzyme-ligand complex stability and reliability were investigated by running 5-nanosecond molecular dynamics simulations. Thorough analysis of the simulation trajectories has shown that enzyme-ligand complexes were stable during the simulation period. Interestingly, the calculated theoretical binding energies of the docked hydroxamic acid inhibitors have shown that the model can discriminate between strong and weaker inhibitors and agrees well with the experimental affinities reported in the literature. The model and the docking methodology can be used in screening virtual libraries for PfHDAC1 inhibitors, since the docking scores have ranked ligands in accordance with experimental binding affinities. Valproic acid calculated theoretical binding energy suggests that it may inhibit PfHDAC1. MDPI 2015-02-11 /pmc/articles/PMC4346934/ /pubmed/25679451 http://dx.doi.org/10.3390/ijms16023915 Text en © 2015 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 license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Elbadawi, Mohamed A. Abdallah
Awadalla, Mohamed Khalid Alhaj
Abdel Hamid, Muzamil Mahdi
Mohamed, Magdi Awadalla
Awad, Talal Ahmed
Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1): An in Silico Approach
title Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1): An in Silico Approach
title_full Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1): An in Silico Approach
title_fullStr Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1): An in Silico Approach
title_full_unstemmed Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1): An in Silico Approach
title_short Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1): An in Silico Approach
title_sort valproic acid as a potential inhibitor of plasmodium falciparum histone deacetylase 1 (pfhdac1): an in silico approach
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346934/
https://www.ncbi.nlm.nih.gov/pubmed/25679451
http://dx.doi.org/10.3390/ijms16023915
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