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Successive Statistical and Structure-Based Modeling to Identify Chemically Novel Kinase Inhibitors
[Image: see text] Kinases are frequently studied in the context of anticancer drugs. Their involvement in cell responses, such as proliferation, differentiation, and apoptosis, makes them interesting subjects in multitarget drug design. In this study, a workflow is presented that models the bioactiv...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525794/ https://www.ncbi.nlm.nih.gov/pubmed/32343143 http://dx.doi.org/10.1021/acs.jcim.9b01204 |
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author | Burggraaff, Lindsey Lenselink, Eelke B. Jespers, Willem van Engelen, Jesper Bongers, Brandon J. González, Marina Gorostiola Liu, Rongfang Hoos, Holger H. van Vlijmen, Herman W. T. IJzerman, Adriaan P. van Westen, Gerard J. P. |
author_facet | Burggraaff, Lindsey Lenselink, Eelke B. Jespers, Willem van Engelen, Jesper Bongers, Brandon J. González, Marina Gorostiola Liu, Rongfang Hoos, Holger H. van Vlijmen, Herman W. T. IJzerman, Adriaan P. van Westen, Gerard J. P. |
author_sort | Burggraaff, Lindsey |
collection | PubMed |
description | [Image: see text] Kinases are frequently studied in the context of anticancer drugs. Their involvement in cell responses, such as proliferation, differentiation, and apoptosis, makes them interesting subjects in multitarget drug design. In this study, a workflow is presented that models the bioactivity spectra for two panels of kinases: (1) inhibition of RET, BRAF, SRC, and S6K, while avoiding inhibition of MKNK1, TTK, ERK8, PDK1, and PAK3, and (2) inhibition of AURKA, PAK1, FGFR1, and LKB1, while avoiding inhibition of PAK3, TAK1, and PIK3CA. Both statistical and structure-based models were included, which were thoroughly benchmarked and optimized. A virtual screening was performed to test the workflow for one of the main targets, RET kinase. This resulted in 5 novel and chemically dissimilar RET inhibitors with remaining RET activity of <60% (at a concentration of 10 μM) and similarities with known RET inhibitors from 0.18 to 0.29 (Tanimoto, ECFP6). The four more potent inhibitors were assessed in a concentration range and proved to be modestly active with a pIC(50) value of 5.1 for the most active compound. The experimental validation of inhibitors for RET strongly indicates that the multitarget workflow is able to detect novel inhibitors for kinases, and hence, this workflow can potentially be applied in polypharmacology modeling. We conclude that this approach can identify new chemical matter for existing targets. Moreover, this workflow can easily be applied to other targets as well. |
format | Online Article Text |
id | pubmed-7525794 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-75257942020-10-01 Successive Statistical and Structure-Based Modeling to Identify Chemically Novel Kinase Inhibitors Burggraaff, Lindsey Lenselink, Eelke B. Jespers, Willem van Engelen, Jesper Bongers, Brandon J. González, Marina Gorostiola Liu, Rongfang Hoos, Holger H. van Vlijmen, Herman W. T. IJzerman, Adriaan P. van Westen, Gerard J. P. J Chem Inf Model [Image: see text] Kinases are frequently studied in the context of anticancer drugs. Their involvement in cell responses, such as proliferation, differentiation, and apoptosis, makes them interesting subjects in multitarget drug design. In this study, a workflow is presented that models the bioactivity spectra for two panels of kinases: (1) inhibition of RET, BRAF, SRC, and S6K, while avoiding inhibition of MKNK1, TTK, ERK8, PDK1, and PAK3, and (2) inhibition of AURKA, PAK1, FGFR1, and LKB1, while avoiding inhibition of PAK3, TAK1, and PIK3CA. Both statistical and structure-based models were included, which were thoroughly benchmarked and optimized. A virtual screening was performed to test the workflow for one of the main targets, RET kinase. This resulted in 5 novel and chemically dissimilar RET inhibitors with remaining RET activity of <60% (at a concentration of 10 μM) and similarities with known RET inhibitors from 0.18 to 0.29 (Tanimoto, ECFP6). The four more potent inhibitors were assessed in a concentration range and proved to be modestly active with a pIC(50) value of 5.1 for the most active compound. The experimental validation of inhibitors for RET strongly indicates that the multitarget workflow is able to detect novel inhibitors for kinases, and hence, this workflow can potentially be applied in polypharmacology modeling. We conclude that this approach can identify new chemical matter for existing targets. Moreover, this workflow can easily be applied to other targets as well. American Chemical Society 2020-04-28 2020-09-28 /pmc/articles/PMC7525794/ /pubmed/32343143 http://dx.doi.org/10.1021/acs.jcim.9b01204 Text en Copyright © 2020 American Chemical Society This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License (http://pubs.acs.org/page/policy/authorchoice_ccbyncnd_termsofuse.html) , which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes. |
spellingShingle | Burggraaff, Lindsey Lenselink, Eelke B. Jespers, Willem van Engelen, Jesper Bongers, Brandon J. González, Marina Gorostiola Liu, Rongfang Hoos, Holger H. van Vlijmen, Herman W. T. IJzerman, Adriaan P. van Westen, Gerard J. P. Successive Statistical and Structure-Based Modeling to Identify Chemically Novel Kinase Inhibitors |
title | Successive Statistical and Structure-Based Modeling
to Identify Chemically Novel Kinase Inhibitors |
title_full | Successive Statistical and Structure-Based Modeling
to Identify Chemically Novel Kinase Inhibitors |
title_fullStr | Successive Statistical and Structure-Based Modeling
to Identify Chemically Novel Kinase Inhibitors |
title_full_unstemmed | Successive Statistical and Structure-Based Modeling
to Identify Chemically Novel Kinase Inhibitors |
title_short | Successive Statistical and Structure-Based Modeling
to Identify Chemically Novel Kinase Inhibitors |
title_sort | successive statistical and structure-based modeling
to identify chemically novel kinase inhibitors |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525794/ https://www.ncbi.nlm.nih.gov/pubmed/32343143 http://dx.doi.org/10.1021/acs.jcim.9b01204 |
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