Discovery of a novel kinase hinge binder fragment by dynamic undocking
| Autor: | Dávid Bajusz, Andrea Scarpino, Anasztázia Hetényi, László Buday, Balázs Merő, Moira Rachman, György M. Keserű, Xavier Barril, Attila Egyed |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
health care facilities
manpower and services education Hinge Pharmaceutical Science Computational biology Biochemistry 03 medical and health sciences 0302 clinical medicine health services administration Drug Discovery Binding site 030304 developmental biology Pharmacology 0303 health sciences Virtual screening Kinase Chemistry Microscale thermophoresis Organic Chemistry Chemical space 3. Good health Docking (molecular) 030220 oncology & carcinogenesis Molecular Medicine Hinge region |
| Zdroj: | RSC Medicinal Chemistry |
| ISSN: | 2632-8682 |
| DOI: | 10.1039/c9md00519f |
| Popis: | A virtual screening workflow for fragment-sized kinase inhibitors is presented, along with a newly identified and validated hinge binder fragment. 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|