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Pharmacophore Model-Based Virtual Screening Workflow for Discovery of Inhibitors Targeting Plasmodium falciparum Hsp90
[Image: see text] Plasmodium falciparum causes the most lethal and widespread form of malaria. Eradication of malaria remains a priority due to the increasing number of cases of drug resistance. The heat shock protein 90 of P. falciparum (PfHsp90) is a validated drug target essential for parasite su...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10586269/ https://www.ncbi.nlm.nih.gov/pubmed/37867657 http://dx.doi.org/10.1021/acsomega.3c04494 |
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author | Mafethe, Ofentse Ntseane, Tlhalefo Dongola, Tendamudzimu Harmfree Shonhai, Addmore Gumede, Njabulo Joyfull Mokoena, Fortunate |
author_facet | Mafethe, Ofentse Ntseane, Tlhalefo Dongola, Tendamudzimu Harmfree Shonhai, Addmore Gumede, Njabulo Joyfull Mokoena, Fortunate |
author_sort | Mafethe, Ofentse |
collection | PubMed |
description | [Image: see text] Plasmodium falciparum causes the most lethal and widespread form of malaria. Eradication of malaria remains a priority due to the increasing number of cases of drug resistance. The heat shock protein 90 of P. falciparum (PfHsp90) is a validated drug target essential for parasite survival. Most PfHsp90 inhibitors bind at the ATP binding pocket found in its N-terminal domain, abolishing the chaperone's activities, which leads to parasite death. The challenge is that the NTD of PfHsp90 is highly conserved, and its disruption requires selective inhibitors that can act without causing off-target human Hsp90 activities. We endeavored to discover selective inhibitors of PfHsp90 using pharmacophore modeling, virtual screening protocols, induced fit docking (IFD), and cell-based and biochemical assays. The pharmacophore model (DHHRR), composed of one hydrogen bond donor, two hydrophobic groups, and two aromatic rings, was used to mine commercial databases for initial hits, which were rescored to 20 potential hits using IFD. Eight of these compounds displayed moderate to high activity toward P. falciparum NF54 (i.e., IC(50)s ranging from 6.0 to 0.14 μM) and averaged >10 in terms of selectivity indices toward CHO and HepG2 cells. Additionally, four compounds inhibited PfHsp90 with greater selectivity than a known inhibitor, harmine, and bound to PfHsp90 with weak to moderate affinity. Our findings support the use of a pharmacophore model to discover diverse chemical scaffolds such as FM2, FM6, F10, and F11 exhibiting anti-Plasmodium activities and serving as valuable new PfHsp90 inhibitors. Optimization of these hits may enable their development into potent leads for future antimalarial drugs. |
format | Online Article Text |
id | pubmed-10586269 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-105862692023-10-20 Pharmacophore Model-Based Virtual Screening Workflow for Discovery of Inhibitors Targeting Plasmodium falciparum Hsp90 Mafethe, Ofentse Ntseane, Tlhalefo Dongola, Tendamudzimu Harmfree Shonhai, Addmore Gumede, Njabulo Joyfull Mokoena, Fortunate ACS Omega [Image: see text] Plasmodium falciparum causes the most lethal and widespread form of malaria. Eradication of malaria remains a priority due to the increasing number of cases of drug resistance. The heat shock protein 90 of P. falciparum (PfHsp90) is a validated drug target essential for parasite survival. Most PfHsp90 inhibitors bind at the ATP binding pocket found in its N-terminal domain, abolishing the chaperone's activities, which leads to parasite death. The challenge is that the NTD of PfHsp90 is highly conserved, and its disruption requires selective inhibitors that can act without causing off-target human Hsp90 activities. We endeavored to discover selective inhibitors of PfHsp90 using pharmacophore modeling, virtual screening protocols, induced fit docking (IFD), and cell-based and biochemical assays. The pharmacophore model (DHHRR), composed of one hydrogen bond donor, two hydrophobic groups, and two aromatic rings, was used to mine commercial databases for initial hits, which were rescored to 20 potential hits using IFD. Eight of these compounds displayed moderate to high activity toward P. falciparum NF54 (i.e., IC(50)s ranging from 6.0 to 0.14 μM) and averaged >10 in terms of selectivity indices toward CHO and HepG2 cells. Additionally, four compounds inhibited PfHsp90 with greater selectivity than a known inhibitor, harmine, and bound to PfHsp90 with weak to moderate affinity. Our findings support the use of a pharmacophore model to discover diverse chemical scaffolds such as FM2, FM6, F10, and F11 exhibiting anti-Plasmodium activities and serving as valuable new PfHsp90 inhibitors. Optimization of these hits may enable their development into potent leads for future antimalarial drugs. American Chemical Society 2023-09-26 /pmc/articles/PMC10586269/ /pubmed/37867657 http://dx.doi.org/10.1021/acsomega.3c04494 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Mafethe, Ofentse Ntseane, Tlhalefo Dongola, Tendamudzimu Harmfree Shonhai, Addmore Gumede, Njabulo Joyfull Mokoena, Fortunate Pharmacophore Model-Based Virtual Screening Workflow for Discovery of Inhibitors Targeting Plasmodium falciparum Hsp90 |
title | Pharmacophore Model-Based
Virtual Screening Workflow
for Discovery of Inhibitors Targeting Plasmodium
falciparum Hsp90 |
title_full | Pharmacophore Model-Based
Virtual Screening Workflow
for Discovery of Inhibitors Targeting Plasmodium
falciparum Hsp90 |
title_fullStr | Pharmacophore Model-Based
Virtual Screening Workflow
for Discovery of Inhibitors Targeting Plasmodium
falciparum Hsp90 |
title_full_unstemmed | Pharmacophore Model-Based
Virtual Screening Workflow
for Discovery of Inhibitors Targeting Plasmodium
falciparum Hsp90 |
title_short | Pharmacophore Model-Based
Virtual Screening Workflow
for Discovery of Inhibitors Targeting Plasmodium
falciparum Hsp90 |
title_sort | pharmacophore model-based
virtual screening workflow
for discovery of inhibitors targeting plasmodium
falciparum hsp90 |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10586269/ https://www.ncbi.nlm.nih.gov/pubmed/37867657 http://dx.doi.org/10.1021/acsomega.3c04494 |
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