Sergio, Ruiz-Carmona, Schmidtke, Peter, Luque, F. Javier et al. (7 more authors) (2017) Dynamic undocking and the quasi-bound state as tools for drug discovery. Nature Chemistry. pp. 201-206. ISSN 1755-4349
Abstract
There is a pressing need for new technologies that improve the efficacy and efficiency of drug discovery. Structure-based methods have contributed towards this goal but they focus on predicting the binding affinity of protein–ligand complexes, which is notoriously difficult. We adopt an alternative approach that evaluates structural, rather than thermodynamic, stability. As bioactive molecules present a static binding mode, we devised dynamic undocking (DUck), a fast computational method to calculate the work necessary to reach a quasi-bound state at which the ligand has just broken the most important native contact with the receptor. This non-equilibrium property is surprisingly effective in virtual screening because true ligands form more-resilient interactions than decoys. Notably, DUck is orthogonal to docking and other ‘thermodynamic’ methods. We demonstrate the potential of the docking–undocking combination in a fragment screening against the molecular chaperone and oncology target Hsp90, for which we obtain novel chemotypes and a hit rate that approaches 40%
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016 Macmillan Publishers Limited. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) |
Depositing User: | Pure (York) |
Date Deposited: | 04 Jan 2017 10:37 |
Last Modified: | 03 Apr 2025 23:09 |
Published Version: | https://doi.org/10.1038/nchem.2660 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1038/nchem.2660 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:110037 |