Issue 5, 2020

Discovery of a novel kinase hinge binder fragment by dynamic undocking

Abstract

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.

Graphical abstract: Discovery of a novel kinase hinge binder fragment by dynamic undocking

Article information

Article type
Research Article
Submitted
06 Nov 2019
Accepted
11 Feb 2020
First published
04 Mar 2020
This article is Open Access
Creative Commons BY-NC license

RSC Med. Chem., 2020,11, 552-558

Discovery of a novel kinase hinge binder fragment by dynamic undocking

M. Rachman, D. Bajusz, A. Hetényi, A. Scarpino, B. Merő, A. Egyed, L. Buday, X. Barril and G. M. Keserű, RSC Med. Chem., 2020, 11, 552 DOI: 10.1039/C9MD00519F

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements