Dynamic undocking and the quasi-bound state as tools for drug discovery

Ruiz-Carmona Sergio, Peter Schmidtke, F. Javier Luque, Lisa Baker, Natalia Matassova, Ben Davis, Stephen Roughley, James Murray, Roderick Eliot Hubbard, Xavier Barril

Research output: Contribution to journalArticlepeer-review


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%
Original languageEnglish
Pages (from-to)201-206
Number of pages6
JournalNature Chemistry
Issue number3
Early online date14 Nov 2016
Publication statusPublished - 1 Mar 2017

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