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Discovery of novel natural products as dual MNK/PIM inhibitors for acute myeloid leukemia treatment: Pharmacophore modeling, molecular docking, and molecular dynamics studies

MNK-2 and PIM-2 kinases play an indispensable role in cell proliferation signaling pathways linked to tyrosine kinase inhibitors resistance. In this study, pharmacophore modeling studies have been conducted on the co-crystalized ligands of MNK-2 and PIM-2 enzyme crystal structures to determine the e...

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Autores principales: Mohamed, Linda M., Eltigani, Maha M., Abdallah, Marwa H., Ghaboosh, Hiba, Bin Jardan, Yousef A., Yusuf, Osman, Elsaman, Tilal, Mohamed, Magdi A., Alzain, Abdulrahim A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9354516/
https://www.ncbi.nlm.nih.gov/pubmed/35936081
http://dx.doi.org/10.3389/fchem.2022.975191
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author Mohamed, Linda M.
Eltigani, Maha M.
Abdallah, Marwa H.
Ghaboosh, Hiba
Bin Jardan, Yousef A.
Yusuf, Osman
Elsaman, Tilal
Mohamed, Magdi A.
Alzain, Abdulrahim A.
author_facet Mohamed, Linda M.
Eltigani, Maha M.
Abdallah, Marwa H.
Ghaboosh, Hiba
Bin Jardan, Yousef A.
Yusuf, Osman
Elsaman, Tilal
Mohamed, Magdi A.
Alzain, Abdulrahim A.
author_sort Mohamed, Linda M.
collection PubMed
description MNK-2 and PIM-2 kinases play an indispensable role in cell proliferation signaling pathways linked to tyrosine kinase inhibitors resistance. In this study, pharmacophore modeling studies have been conducted on the co-crystalized ligands of MNK-2 and PIM-2 enzyme crystal structures to determine the essential features required for the identification of potential dual inhibitors. The obtained pharmacophore features were then screened against a library of 270,540 natural products from the ZINC database. The matched natural molecules were docked into the binding sites of MNK-2 and PIM-2 enzymes. The compounds with high docking scores with the two enzymes were further subjected to MM-GBSA calculations and ADME prediction. This led to the identification of compound 1 (ZINC000085569211), compound 2 (ZINC000085569178), and compound 3 (ZINC000085569190), with better docking scores compared to the reference co-crystallized ligands of MNK-2 and PIM-2. Moreover, compounds 1‒3 displayed better MM-GBSA binding free energies compared to the reference ligands. Finally, molecular dynamics (MD) study was used to assess the interaction stability of the compounds with MNK-2. To this end, compounds 1 and 3 bound strongly to the target during the whole period of MD simulation. The findings of the current study may further help the researchers in the discovery of novel molecules against MNK-2 and PIM-2.
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spelling pubmed-93545162022-08-06 Discovery of novel natural products as dual MNK/PIM inhibitors for acute myeloid leukemia treatment: Pharmacophore modeling, molecular docking, and molecular dynamics studies Mohamed, Linda M. Eltigani, Maha M. Abdallah, Marwa H. Ghaboosh, Hiba Bin Jardan, Yousef A. Yusuf, Osman Elsaman, Tilal Mohamed, Magdi A. Alzain, Abdulrahim A. Front Chem Chemistry MNK-2 and PIM-2 kinases play an indispensable role in cell proliferation signaling pathways linked to tyrosine kinase inhibitors resistance. In this study, pharmacophore modeling studies have been conducted on the co-crystalized ligands of MNK-2 and PIM-2 enzyme crystal structures to determine the essential features required for the identification of potential dual inhibitors. The obtained pharmacophore features were then screened against a library of 270,540 natural products from the ZINC database. The matched natural molecules were docked into the binding sites of MNK-2 and PIM-2 enzymes. The compounds with high docking scores with the two enzymes were further subjected to MM-GBSA calculations and ADME prediction. This led to the identification of compound 1 (ZINC000085569211), compound 2 (ZINC000085569178), and compound 3 (ZINC000085569190), with better docking scores compared to the reference co-crystallized ligands of MNK-2 and PIM-2. Moreover, compounds 1‒3 displayed better MM-GBSA binding free energies compared to the reference ligands. Finally, molecular dynamics (MD) study was used to assess the interaction stability of the compounds with MNK-2. To this end, compounds 1 and 3 bound strongly to the target during the whole period of MD simulation. The findings of the current study may further help the researchers in the discovery of novel molecules against MNK-2 and PIM-2. Frontiers Media S.A. 2022-07-22 /pmc/articles/PMC9354516/ /pubmed/35936081 http://dx.doi.org/10.3389/fchem.2022.975191 Text en Copyright © 2022 Mohamed, Eltigani, Abdallah, Ghaboosh, Bin Jardan, Yusuf, Elsaman, Mohamed and Alzain. 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 Chemistry
Mohamed, Linda M.
Eltigani, Maha M.
Abdallah, Marwa H.
Ghaboosh, Hiba
Bin Jardan, Yousef A.
Yusuf, Osman
Elsaman, Tilal
Mohamed, Magdi A.
Alzain, Abdulrahim A.
Discovery of novel natural products as dual MNK/PIM inhibitors for acute myeloid leukemia treatment: Pharmacophore modeling, molecular docking, and molecular dynamics studies
title Discovery of novel natural products as dual MNK/PIM inhibitors for acute myeloid leukemia treatment: Pharmacophore modeling, molecular docking, and molecular dynamics studies
title_full Discovery of novel natural products as dual MNK/PIM inhibitors for acute myeloid leukemia treatment: Pharmacophore modeling, molecular docking, and molecular dynamics studies
title_fullStr Discovery of novel natural products as dual MNK/PIM inhibitors for acute myeloid leukemia treatment: Pharmacophore modeling, molecular docking, and molecular dynamics studies
title_full_unstemmed Discovery of novel natural products as dual MNK/PIM inhibitors for acute myeloid leukemia treatment: Pharmacophore modeling, molecular docking, and molecular dynamics studies
title_short Discovery of novel natural products as dual MNK/PIM inhibitors for acute myeloid leukemia treatment: Pharmacophore modeling, molecular docking, and molecular dynamics studies
title_sort discovery of novel natural products as dual mnk/pim inhibitors for acute myeloid leukemia treatment: pharmacophore modeling, molecular docking, and molecular dynamics studies
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9354516/
https://www.ncbi.nlm.nih.gov/pubmed/35936081
http://dx.doi.org/10.3389/fchem.2022.975191
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