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

Nature Chemistry volume 9, pages 201–206 (2017)Cite this article

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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%.

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Figure 1: Calculation of WQB.
Figure 2: Application of the quasi-bound approximation to ligand ranking.
Figure 3: Additional analyses of the prospective application of DUck in Hsp90.
Figure 4: Experimental (grey) and predicted (orange) binding modes of the fragment hits.

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Acknowledgements

We thank C. Galdeano for helpful discussions and manuscript revision. We thank the Barcelona Supercomputing Center for access to computational resources. This work was financed by the Spanish Ministerio de Economia (SAF2012-33481, SAF2015-68749-R), the Catalan government (2014 SGR 1189) and the ICREA Academia program (F.J.L.).

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Authors and Affiliations

  1. Institut de Biomedicina de la Universitat de Barcelona (IBUB) and Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII s/n, Barcelona, 08028, Spain

    Sergio Ruiz-Carmona, F. Javier Luque & Xavier Barril

  2. Discngine, 33 rue du Fauburg Saint-Antoine, Paris, 75011, France

    Peter Schmidtke

  3. Vernalis (R&D) Ltd, Granta Park, Cambridge, CB21 6GB, UK

    Lisa Baker, Natalia Matassova, Ben Davis, Stephen Roughley, James Murray & Rod Hubbard

  4. YSBL, University of York, Heslington, YO10 5DD, York, UK

    Rod Hubbard

  5. Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23, Barcelona, 08010, Spain

    Xavier Barril

Authors
  1. Sergio Ruiz-Carmona
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  2. Peter Schmidtke
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Contributions

F.J.L., R.H. and X.B. conceived the overall strategy of the study. P.S. and X.B. conceived and implemented the DUck approach. S.R.C. and X.B. carried out and analysed all the computational work. B.D. performed NMR experiments. L.B. performed X-ray crystallography experiments. N.M. performed SPR experiments. All the authors discussed the results, designed experiments and wrote the paper.

Corresponding author

Correspondence to Xavier Barril.

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The authors declare no competing financial interests.

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Ruiz-Carmona, S., Schmidtke, P., Luque, F. et al. Dynamic undocking and the quasi-bound state as tools for drug discovery. Nature Chem 9, 201–206 (2017). https://doi.org/10.1038/nchem.2660

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