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Water molecules in protein–ligand interfaces. Evaluation of software tools and SAR comparison

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Abstract

Targeting the interaction with or displacement of the ‘right’ water molecule can significantly increase inhibitor potency in structure-guided drug design. Multiple computational approaches exist to predict which waters should be targeted for displacement to achieve the largest gain in potency. However, the relative success of different methods remains underexplored. Here, we present a comparison of the ability of five water prediction programs (3D-RISM, SZMAP, WaterFLAP, WaterRank, and WaterMap) to predict crystallographic water locations, calculate their binding free energies, and to relate differences in these energies to observed changes in potency. The structural cohort included nine Bruton’s Tyrosine Kinase (BTK) structures, and nine bromodomain structures. Each program accurately predicted the locations of most crystallographic water molecules. However, the predicted binding free energies correlated poorly with the observed changes in inhibitor potency when solvent atoms were displaced by chemical changes in closely related compounds.

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Abbreviations

BRD:

Bromodomain

BTK:

Bruton’s Tyrosine Kinase

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Acknowledgements

We thank Matthias Rarey for his support during the project. We thank Terry Crawford, Shumei Wang, Lina Chan, Alex Cote, Chris Nasveschuk, and Matthew Berlin for their syntheses of BRD and TAF small molecule inhibitors. We also acknowledge Wendy Young, Gina Wang, Kevin Currie, and the other chemists at CGI Pharmaceuticals (now Gilead) for their support of the BTK program and syntheses of BTK small molecule inhibitors. Additionally, we thank Laura E. Zawadzke and Eneida Pardo of Constellation Pharmaceuticals for their help assaying the BRD and TAF inhibitors; and Julie DiPaolo for conducting the BTK Lanthascreen assays. Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center (SBC) at the Advanced Photon Source. SBC-CAT is operated by UChicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. The Berkeley Center for Structural Biology is supported in part by the National Institutes of Health, National Institute of General Medical Sciences, and the Howard Hughes Medical Institute. The Advanced Light Source is a Department of Energy Office of Science User Facility under Contract No. DE-AC02-05CH11231.

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Author notes

  1. Vickie Tsui

    Present address: Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA

  2. Yong Tang

    Present address: Relay Therapeutics, 215 First Street, 3rd Floor, Cambridge, MA, 02142, USA

Authors and Affiliations

  1. Universität Hamburg, ZBH - Center for Bioinformatics, Bundesstraße 43, 20146, Hamburg, Germany

    Eva Nittinger

  2. Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA

    Paul Gibbons, Charles Eigenbrot, Brigitte Maurer, Christine L. Yu, James R. Kiefer, Jeremy Murray, Daniel F. Ortwine & Vickie Tsui

  3. Beryllium Discovery, 7869 NE Day Road West, Bainbridge Island, WA, 98110, USA

    Doug R. Davies

  4. F. Hoffman-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland

    Andreas Kuglstatter

  5. Constellation Pharmaceuticals, 215 First Street, Cambridge, MA, 02142, USA

    Yong Tang

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  1. Eva Nittinger
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Contributions

EN wrote the manuscript, developed the strategy and conducted the evaluations. DD, CE, JK, JM, and YT determined the BRD and BTK crystal structures used in the analysis. DFO and PG have contributed to the manuscript and have supervised the project. VT also assisted in project supervision.

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Correspondence to Eva Nittinger, Paul Gibbons or Charles Eigenbrot.

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Nittinger, E., Gibbons, P., Eigenbrot, C. et al. Water molecules in protein–ligand interfaces. Evaluation of software tools and SAR comparison. J Comput Aided Mol Des 33, 307–330 (2019). https://doi.org/10.1007/s10822-019-00187-y

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