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Benzimidazole inhibitors of the protein kinase CHK2: Clarification of the binding mode by flexible side chain docking and protein–ligand crystallography

Two closely related binding modes have previously been proposed for the ATP-competitive benzimidazole class of checkpoint kinase 2 (CHK2) inhibitors; however, neither binding mode is entirely consistent with the reported SAR. Unconstrained rigid docking of benzimidazole ligands into representative C...

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Autores principales: Matijssen, Cornelis, Silva-Santisteban, M. Cris, Westwood, Isaac M., Siddique, Samerene, Choi, Vanessa, Sheldrake, Peter, van Montfort, Rob L.M., Blagg, Julian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3778940/
https://www.ncbi.nlm.nih.gov/pubmed/23058106
http://dx.doi.org/10.1016/j.bmc.2012.09.024
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author Matijssen, Cornelis
Silva-Santisteban, M. Cris
Westwood, Isaac M.
Siddique, Samerene
Choi, Vanessa
Sheldrake, Peter
van Montfort, Rob L.M.
Blagg, Julian
author_facet Matijssen, Cornelis
Silva-Santisteban, M. Cris
Westwood, Isaac M.
Siddique, Samerene
Choi, Vanessa
Sheldrake, Peter
van Montfort, Rob L.M.
Blagg, Julian
author_sort Matijssen, Cornelis
collection PubMed
description Two closely related binding modes have previously been proposed for the ATP-competitive benzimidazole class of checkpoint kinase 2 (CHK2) inhibitors; however, neither binding mode is entirely consistent with the reported SAR. Unconstrained rigid docking of benzimidazole ligands into representative CHK2 protein crystal structures reveals an alternative binding mode involving a water-mediated interaction with the hinge region; docking which incorporates protein side chain flexibility for selected residues in the ATP binding site resulted in a refinement of the water-mediated hinge binding mode that is consistent with observed SAR. The flexible docking results are in good agreement with the crystal structures of four exemplar benzimidazole ligands bound to CHK2 which unambiguously confirmed the binding mode of these inhibitors, including the water-mediated interaction with the hinge region, and which is significantly different from binding modes previously postulated in the literature.
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spelling pubmed-37789402013-09-23 Benzimidazole inhibitors of the protein kinase CHK2: Clarification of the binding mode by flexible side chain docking and protein–ligand crystallography Matijssen, Cornelis Silva-Santisteban, M. Cris Westwood, Isaac M. Siddique, Samerene Choi, Vanessa Sheldrake, Peter van Montfort, Rob L.M. Blagg, Julian Bioorg Med Chem Article Two closely related binding modes have previously been proposed for the ATP-competitive benzimidazole class of checkpoint kinase 2 (CHK2) inhibitors; however, neither binding mode is entirely consistent with the reported SAR. Unconstrained rigid docking of benzimidazole ligands into representative CHK2 protein crystal structures reveals an alternative binding mode involving a water-mediated interaction with the hinge region; docking which incorporates protein side chain flexibility for selected residues in the ATP binding site resulted in a refinement of the water-mediated hinge binding mode that is consistent with observed SAR. The flexible docking results are in good agreement with the crystal structures of four exemplar benzimidazole ligands bound to CHK2 which unambiguously confirmed the binding mode of these inhibitors, including the water-mediated interaction with the hinge region, and which is significantly different from binding modes previously postulated in the literature. Elsevier Science 2012-11-15 /pmc/articles/PMC3778940/ /pubmed/23058106 http://dx.doi.org/10.1016/j.bmc.2012.09.024 Text en © 2012 Elsevier Ltd. https://creativecommons.org/licenses/by/3.0/ Open Access under CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/) license
spellingShingle Article
Matijssen, Cornelis
Silva-Santisteban, M. Cris
Westwood, Isaac M.
Siddique, Samerene
Choi, Vanessa
Sheldrake, Peter
van Montfort, Rob L.M.
Blagg, Julian
Benzimidazole inhibitors of the protein kinase CHK2: Clarification of the binding mode by flexible side chain docking and protein–ligand crystallography
title Benzimidazole inhibitors of the protein kinase CHK2: Clarification of the binding mode by flexible side chain docking and protein–ligand crystallography
title_full Benzimidazole inhibitors of the protein kinase CHK2: Clarification of the binding mode by flexible side chain docking and protein–ligand crystallography
title_fullStr Benzimidazole inhibitors of the protein kinase CHK2: Clarification of the binding mode by flexible side chain docking and protein–ligand crystallography
title_full_unstemmed Benzimidazole inhibitors of the protein kinase CHK2: Clarification of the binding mode by flexible side chain docking and protein–ligand crystallography
title_short Benzimidazole inhibitors of the protein kinase CHK2: Clarification of the binding mode by flexible side chain docking and protein–ligand crystallography
title_sort benzimidazole inhibitors of the protein kinase chk2: clarification of the binding mode by flexible side chain docking and protein–ligand crystallography
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3778940/
https://www.ncbi.nlm.nih.gov/pubmed/23058106
http://dx.doi.org/10.1016/j.bmc.2012.09.024
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