ChemRxiv
These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
1/1
2 files

KinFragLib: Exploring the Kinase Inhibitor Space Using Subpocket-Focused Fragmentation and Recombination

preprint
submitted on 23.07.2020 and posted on 24.07.2020 by Dominique Sydow, Paula Schmiel, Jérémie Mortier, Andrea Volkamer
Protein kinases play a crucial role in many cell signaling processes, making them one of the most important families of drug targets. In this context, fragment-based drug design strategies have been successfully applied to develop novel kinase inhibitors, usually following a knowledge-driven approach to optimize a focused set of fragments to a potent kinase inhibitor.
Alternatively, KinFragLib is a new method that allows to explore and extend the chemical space of kinase inhibitors using data-driven fragmentation and recombination, built on available structural kinome data from the KLIFS database for over 2,500 kinase DFG-in complexes. The computational fragmentation method splits the co-crystallized non-covalent kinase inhibitors into fragments with respect to their 3D proximity to six predefined functionally relevant subpocket centers. The resulting fragment library consists of six subpocket pools with over 7,000 fragments, available at https://github.com/volkamerlab/KinFragLib.
KinFragLib offers two main applications: (i) In-depth analyses of the chemical space of known kinase inhibitors, subpocket characteristics and connections, as well as (ii) subpocket-informed recombination of fragments to generate potential novel inhibitors. The latter showed that recombining only a subset of 624 representative fragments generated a combinatorial library of 6.7 million molecules, containing, besides some known kinase inhibitors, more than 99% novel chemical matter compared to ChEMBL and 63% molecules compliant with Lipinski's rule of five.

Funding

Deutsche Forschungsgemeinschaft (VO 2353/1-1)

Bundesministerium für Bildung und Forschung (031A262C)

History

Email Address of Submitting Author

andrea.volkamer@charite.de

Institution

Charité - Universitätsmedizin Berlin

Country

Germany

ORCID For Submitting Author

0000-0003-4205-8705

Declaration of Conflict of Interest

None

Version Notes

Version v1.0.0

Licence

Exports