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In silico identification of modulators of J domain protein-Hsp70 interactions in Plasmodium falciparum: a drug repurposing strategy against malaria
Plasmodium falciparum is a unicellular, intracellular protozoan parasite, and the causative agent of malaria in humans, a deadly vector borne infectious disease. A key phase of malaria pathology, is the invasion of human erythrocytes, resulting in drastic remodeling by exported parasite proteins, in...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10445141/ https://www.ncbi.nlm.nih.gov/pubmed/37621993 http://dx.doi.org/10.3389/fmolb.2023.1158912 |
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author | Singh, Harpreet Almaazmi, Shaikha Y. Dutta, Tanima Keyzers, Robert A. Blatch, Gregory L. |
author_facet | Singh, Harpreet Almaazmi, Shaikha Y. Dutta, Tanima Keyzers, Robert A. Blatch, Gregory L. |
author_sort | Singh, Harpreet |
collection | PubMed |
description | Plasmodium falciparum is a unicellular, intracellular protozoan parasite, and the causative agent of malaria in humans, a deadly vector borne infectious disease. A key phase of malaria pathology, is the invasion of human erythrocytes, resulting in drastic remodeling by exported parasite proteins, including molecular chaperones and co-chaperones. The survival of the parasite within the human host is mediated by P. falciparum heat shock protein 70s (PfHsp70s) and J domain proteins (PfJDPs), functioning as chaperones-co-chaperones partnerships. Two complexes have been shown to be important for survival and pathology of the malaria parasite: PfHsp70-x-PFE0055c (exported); and PfHsp70-2-PfSec63 (endoplasmic reticulum). Virtual screening was conducted on the drug repurposing library, the Pandemic Response Box, to identify small-molecules that could specifically disrupt these chaperone complexes. Five top ranked compounds possessing preferential binding affinity for the malarial chaperone system compared to the human system, were identified; three top PfHsp70-PfJDP binders, MBX 1641, zoliflodacin and itraconazole; and two top J domain binders, ezetimibe and a benzo-diazepinone. These compounds were validated by repeat molecular dockings and molecular dynamics simulation, resulting in all the compounds, except for MBX 1461, being confirmed to bind preferentially to the malarial chaperone system. A detailed contact analysis of the PfHsp70-PfJDP binders identified two different types of modulators, those that potentially inhibit complex formation (MBX 1461), and those that potentially stabilize the complex (zoliflodacin and itraconazole). These data suggested that zoliflodacin and itraconazole are potential novel modulators specific to the malarial system. A detailed contact analysis of the J domain binders (ezetimibe and the benzo-diazepinone), revealed that they bound with not only greater affinity but also a better pose to the malarial J domain compared to that of the human system. These data suggested that ezetimibe and the benzo-diazepinone are potential specific inhibitors of the malarial chaperone system. Both itraconazole and ezetimibe are FDA-approved drugs, possess anti-malarial activity and have recently been repurposed for the treatment of cancer. This is the first time that such drug-like compounds have been identified as potential modulators of PfHsp70-PfJDP complexes, and they represent novel candidates for validation and development into anti-malarial drugs. |
format | Online Article Text |
id | pubmed-10445141 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-104451412023-08-24 In silico identification of modulators of J domain protein-Hsp70 interactions in Plasmodium falciparum: a drug repurposing strategy against malaria Singh, Harpreet Almaazmi, Shaikha Y. Dutta, Tanima Keyzers, Robert A. Blatch, Gregory L. Front Mol Biosci Molecular Biosciences Plasmodium falciparum is a unicellular, intracellular protozoan parasite, and the causative agent of malaria in humans, a deadly vector borne infectious disease. A key phase of malaria pathology, is the invasion of human erythrocytes, resulting in drastic remodeling by exported parasite proteins, including molecular chaperones and co-chaperones. The survival of the parasite within the human host is mediated by P. falciparum heat shock protein 70s (PfHsp70s) and J domain proteins (PfJDPs), functioning as chaperones-co-chaperones partnerships. Two complexes have been shown to be important for survival and pathology of the malaria parasite: PfHsp70-x-PFE0055c (exported); and PfHsp70-2-PfSec63 (endoplasmic reticulum). Virtual screening was conducted on the drug repurposing library, the Pandemic Response Box, to identify small-molecules that could specifically disrupt these chaperone complexes. Five top ranked compounds possessing preferential binding affinity for the malarial chaperone system compared to the human system, were identified; three top PfHsp70-PfJDP binders, MBX 1641, zoliflodacin and itraconazole; and two top J domain binders, ezetimibe and a benzo-diazepinone. These compounds were validated by repeat molecular dockings and molecular dynamics simulation, resulting in all the compounds, except for MBX 1461, being confirmed to bind preferentially to the malarial chaperone system. A detailed contact analysis of the PfHsp70-PfJDP binders identified two different types of modulators, those that potentially inhibit complex formation (MBX 1461), and those that potentially stabilize the complex (zoliflodacin and itraconazole). These data suggested that zoliflodacin and itraconazole are potential novel modulators specific to the malarial system. A detailed contact analysis of the J domain binders (ezetimibe and the benzo-diazepinone), revealed that they bound with not only greater affinity but also a better pose to the malarial J domain compared to that of the human system. These data suggested that ezetimibe and the benzo-diazepinone are potential specific inhibitors of the malarial chaperone system. Both itraconazole and ezetimibe are FDA-approved drugs, possess anti-malarial activity and have recently been repurposed for the treatment of cancer. This is the first time that such drug-like compounds have been identified as potential modulators of PfHsp70-PfJDP complexes, and they represent novel candidates for validation and development into anti-malarial drugs. Frontiers Media S.A. 2023-08-09 /pmc/articles/PMC10445141/ /pubmed/37621993 http://dx.doi.org/10.3389/fmolb.2023.1158912 Text en Copyright © 2023 Singh, Almaazmi, Dutta, Keyzers and Blatch. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Molecular Biosciences Singh, Harpreet Almaazmi, Shaikha Y. Dutta, Tanima Keyzers, Robert A. Blatch, Gregory L. In silico identification of modulators of J domain protein-Hsp70 interactions in Plasmodium falciparum: a drug repurposing strategy against malaria |
title |
In silico identification of modulators of J domain protein-Hsp70 interactions in Plasmodium falciparum: a drug repurposing strategy against malaria |
title_full |
In silico identification of modulators of J domain protein-Hsp70 interactions in Plasmodium falciparum: a drug repurposing strategy against malaria |
title_fullStr |
In silico identification of modulators of J domain protein-Hsp70 interactions in Plasmodium falciparum: a drug repurposing strategy against malaria |
title_full_unstemmed |
In silico identification of modulators of J domain protein-Hsp70 interactions in Plasmodium falciparum: a drug repurposing strategy against malaria |
title_short |
In silico identification of modulators of J domain protein-Hsp70 interactions in Plasmodium falciparum: a drug repurposing strategy against malaria |
title_sort | in silico identification of modulators of j domain protein-hsp70 interactions in plasmodium falciparum: a drug repurposing strategy against malaria |
topic | Molecular Biosciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10445141/ https://www.ncbi.nlm.nih.gov/pubmed/37621993 http://dx.doi.org/10.3389/fmolb.2023.1158912 |
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