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Discovery of a novel kinase hinge binder fragment by dynamic undocking

One of the key motifs of type I kinase inhibitors is their interactions with the hinge region of ATP binding sites. These interactions contribute significantly to the potency of the inhibitors; however, only a tiny fraction of the available chemical space has been explored with kinase inhibitors rep...

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Autores principales: Rachman, Moira, Bajusz, Dávid, Hetényi, Anasztázia, Scarpino, Andrea, Merő, Balázs, Egyed, Attila, Buday, László, Barril, Xavier, Keserű, György M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royal Society of Chemistry 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593776/
https://www.ncbi.nlm.nih.gov/pubmed/33479656
http://dx.doi.org/10.1039/c9md00519f
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author Rachman, Moira
Bajusz, Dávid
Hetényi, Anasztázia
Scarpino, Andrea
Merő, Balázs
Egyed, Attila
Buday, László
Barril, Xavier
Keserű, György M.
author_facet Rachman, Moira
Bajusz, Dávid
Hetényi, Anasztázia
Scarpino, Andrea
Merő, Balázs
Egyed, Attila
Buday, László
Barril, Xavier
Keserű, György M.
author_sort Rachman, Moira
collection PubMed
description One of the key motifs of type I kinase inhibitors is their interactions with the hinge region of ATP binding sites. These interactions contribute significantly to the potency of the inhibitors; however, only a tiny fraction of the available chemical space has been explored with kinase inhibitors reported in the last twenty years. This paper describes a workflow utilizing docking with rDock and dynamic undocking (DUck) for the virtual screening of fragment libraries in order to identify fragments that bind to the kinase hinge region. We have identified 8-amino-2H-isoquinolin-1-one (MR1), a novel and potent hinge binding fragment, which was experimentally tested on a diverse set of kinases, and is hereby suggested for future fragment growing or merging efforts against various kinases, particularly MELK. Direct binding of MR1 to MELK was confirmed by STD-NMR, and its binding to the ATP-pocket was confirmed by a new competitive binding assay based on microscale thermophoresis.
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spelling pubmed-75937762020-11-02 Discovery of a novel kinase hinge binder fragment by dynamic undocking Rachman, Moira Bajusz, Dávid Hetényi, Anasztázia Scarpino, Andrea Merő, Balázs Egyed, Attila Buday, László Barril, Xavier Keserű, György M. RSC Med Chem Chemistry One of the key motifs of type I kinase inhibitors is their interactions with the hinge region of ATP binding sites. These interactions contribute significantly to the potency of the inhibitors; however, only a tiny fraction of the available chemical space has been explored with kinase inhibitors reported in the last twenty years. This paper describes a workflow utilizing docking with rDock and dynamic undocking (DUck) for the virtual screening of fragment libraries in order to identify fragments that bind to the kinase hinge region. We have identified 8-amino-2H-isoquinolin-1-one (MR1), a novel and potent hinge binding fragment, which was experimentally tested on a diverse set of kinases, and is hereby suggested for future fragment growing or merging efforts against various kinases, particularly MELK. Direct binding of MR1 to MELK was confirmed by STD-NMR, and its binding to the ATP-pocket was confirmed by a new competitive binding assay based on microscale thermophoresis. Royal Society of Chemistry 2020-03-04 /pmc/articles/PMC7593776/ /pubmed/33479656 http://dx.doi.org/10.1039/c9md00519f Text en This journal is © The Royal Society of Chemistry 2020 http://creativecommons.org/licenses/by-nc/3.0/ This article is freely available. This article is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported Licence (CC BY-NC 3.0)
spellingShingle Chemistry
Rachman, Moira
Bajusz, Dávid
Hetényi, Anasztázia
Scarpino, Andrea
Merő, Balázs
Egyed, Attila
Buday, László
Barril, Xavier
Keserű, György M.
Discovery of a novel kinase hinge binder fragment by dynamic undocking
title Discovery of a novel kinase hinge binder fragment by dynamic undocking
title_full Discovery of a novel kinase hinge binder fragment by dynamic undocking
title_fullStr Discovery of a novel kinase hinge binder fragment by dynamic undocking
title_full_unstemmed Discovery of a novel kinase hinge binder fragment by dynamic undocking
title_short Discovery of a novel kinase hinge binder fragment by dynamic undocking
title_sort discovery of a novel kinase hinge binder fragment by dynamic undocking
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593776/
https://www.ncbi.nlm.nih.gov/pubmed/33479656
http://dx.doi.org/10.1039/c9md00519f
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