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Identification and validation of novel microtubule suppressors with an imidazopyridine scaffold through structure-based virtual screening and docking
Targeting the colchicine binding site of α/β tubulin microtubules can lead to suppression of microtubule dynamics, cell cycle arrest and apoptosis. Therefore, the development of microtubule (MT) inhibitors is considered a promising route to anticancer agents. Our approach to identify novel scaffolds...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
RSC
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9384815/ https://www.ncbi.nlm.nih.gov/pubmed/36092142 http://dx.doi.org/10.1039/d1md00392e |
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author | Elseginy, Samia A. Oliveira, A. Sofia F. Shoemark, Deborah K. Sessions, Richard B. |
author_facet | Elseginy, Samia A. Oliveira, A. Sofia F. Shoemark, Deborah K. Sessions, Richard B. |
author_sort | Elseginy, Samia A. |
collection | PubMed |
description | Targeting the colchicine binding site of α/β tubulin microtubules can lead to suppression of microtubule dynamics, cell cycle arrest and apoptosis. Therefore, the development of microtubule (MT) inhibitors is considered a promising route to anticancer agents. Our approach to identify novel scaffolds as MT inhibitors depends on a 3D-structure-based pharmacophore approach and docking using three programs MOE, Autodock and BUDE (Bristol University Docking Engine) to screen a library of virtual compounds. From this work we identified the compound 7-(3-hydroxy-4-methoxy-phenyl)-3-(3-trifluoromethyl-phenyl)-6,7-dihydro-3H-imidazo[4,5-b]pyridin-5-ol (6) as a novel inhibitor scaffold. This compound inhibited several types of cancer cell proliferation at low micromolar concentrations with low toxicity. Compound 6 caused cell cycle arrest in the G2/M phase and blocked tubulin polymerization at low micromolar concentration (IC(50) = 6.1 ±0.1 μM), inducing apoptosis via activation of caspase 9, increasing the level of the pro-apoptotic protein Bax and decreasing the level of the anti-apoptotic protein Bcl2. In summary, our approach identified a lead compound with potential antimitotic and antiproliferative activity. |
format | Online Article Text |
id | pubmed-9384815 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | RSC |
record_format | MEDLINE/PubMed |
spelling | pubmed-93848152022-09-08 Identification and validation of novel microtubule suppressors with an imidazopyridine scaffold through structure-based virtual screening and docking Elseginy, Samia A. Oliveira, A. Sofia F. Shoemark, Deborah K. Sessions, Richard B. RSC Med Chem Chemistry Targeting the colchicine binding site of α/β tubulin microtubules can lead to suppression of microtubule dynamics, cell cycle arrest and apoptosis. Therefore, the development of microtubule (MT) inhibitors is considered a promising route to anticancer agents. Our approach to identify novel scaffolds as MT inhibitors depends on a 3D-structure-based pharmacophore approach and docking using three programs MOE, Autodock and BUDE (Bristol University Docking Engine) to screen a library of virtual compounds. From this work we identified the compound 7-(3-hydroxy-4-methoxy-phenyl)-3-(3-trifluoromethyl-phenyl)-6,7-dihydro-3H-imidazo[4,5-b]pyridin-5-ol (6) as a novel inhibitor scaffold. This compound inhibited several types of cancer cell proliferation at low micromolar concentrations with low toxicity. Compound 6 caused cell cycle arrest in the G2/M phase and blocked tubulin polymerization at low micromolar concentration (IC(50) = 6.1 ±0.1 μM), inducing apoptosis via activation of caspase 9, increasing the level of the pro-apoptotic protein Bax and decreasing the level of the anti-apoptotic protein Bcl2. In summary, our approach identified a lead compound with potential antimitotic and antiproliferative activity. RSC 2022-05-18 /pmc/articles/PMC9384815/ /pubmed/36092142 http://dx.doi.org/10.1039/d1md00392e Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (https://creativecommons.org/licenses/by/3.0/) . You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given. |
spellingShingle | Chemistry Elseginy, Samia A. Oliveira, A. Sofia F. Shoemark, Deborah K. Sessions, Richard B. Identification and validation of novel microtubule suppressors with an imidazopyridine scaffold through structure-based virtual screening and docking |
title | Identification and validation of novel microtubule suppressors with an imidazopyridine scaffold through structure-based virtual screening and docking |
title_full | Identification and validation of novel microtubule suppressors with an imidazopyridine scaffold through structure-based virtual screening and docking |
title_fullStr | Identification and validation of novel microtubule suppressors with an imidazopyridine scaffold through structure-based virtual screening and docking |
title_full_unstemmed | Identification and validation of novel microtubule suppressors with an imidazopyridine scaffold through structure-based virtual screening and docking |
title_short | Identification and validation of novel microtubule suppressors with an imidazopyridine scaffold through structure-based virtual screening and docking |
title_sort | identification and validation of novel microtubule suppressors with an imidazopyridine scaffold through structure-based virtual screening and docking |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9384815/ https://www.ncbi.nlm.nih.gov/pubmed/36092142 http://dx.doi.org/10.1039/d1md00392e |
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