Water molecules in protein–ligand interfaces. Evaluation of software tools and SAR comparison
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.
KeywordsWater Water prediction Water placement Water scoring 3D-RISM SZMAP WaterFLAP WaterMap WaterRank BTK Bruton’s Tyrosine kinase BRD Bromodomain
Bruton’s Tyrosine Kinase
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.
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.
Compliance with ethical standards
Conflict of interest
The authors declare no competing financial interest.
- 21.Chrencik JE, Patny A, Leung IK, Korniski B, Emmons TL, Hall T, Weinberg RA, Gormley JA, Williams JM, Day JE, Hirsch JL, Benson TE (2010) Structural and thermodynamic characterization of the TYK2 and JAK3 Kinase domains in complex with CP-690550 and CMP-6. J Mol Biol 400(3):413–433. https://doi.org/10.1016/j.jmb.2010.05.020 Google Scholar
- 23.Repasky MP, Murphy RB, Banks JL, Greenwood JR, Tubert-Brohman I, Bhat S, Friesner RA (2012) Docking performance of the glide program as evaluated on the Astex and DUD datasets: a complete set of glide SP results and selected results for a new scoring function integrating WaterMap and glide. J Comput Aided Mol Des 26(6):787–799. https://doi.org/10.1007/s10822-012-9575-9 Google Scholar
- 25.Nguyen CN, Cruz A, Gilson MK, Kurtzman T (2014) Thermodynamics of water in an enzyme active site: grid-based hydration analysis of coagulation factor Xa. J Chem Theory Comput 10(7):2769–2780Google Scholar
- 26.Bodnarchuk MS, Viner R, Michel J, Essex JW (2014) Strategies to calculate water binding free energies in protein–ligand complexes. J Chem Inform Model 54:1623–1633Google Scholar
- 32.Crawford TD, Tsui V, Flynn EM, Wang S, Taylor AM, Côté A, Audia JE, Beresini MH, Burdick DJ, Cummings R, Dakin LA, Cochran AG (2016) Diving into the water: inducible binding conformations for BRD4, TAF1(2), BRD9, and CECR2 bromodomains. J Med Chem 59(11):5391–5402. https://doi.org/10.1021/acs.jmedchem.6b00264 Google Scholar
- 33.Albrecht BK, Gehling VS, Hewitt MC, Vaswani RG, Côté A, Leblanc Y, Nasveschuk CG, Bellon S, Bergeron L, Campbell R, Cantone N, Audia JE (2016) Identification of a benzoisoxazoloazepine inhibitor (CPI-0610) of the bromodomain and extra-terminal (BET) family as a candidate for human clinical trials. J Med Chem 59(4):1330–1339. https://doi.org/10.1021/acs.jmedchem.5b01882 Google Scholar
- 34.Johnson AR, Kohli PB, Katewa A, Gogol E, Belmont LD, Choy R, Penuel E, Burton L, Eigenbrot C, Yu C, Ortwine DF, Young WB (2016) Battling Btk mutants with noncovalent inhibitors that overcome Cys481 and Thr474 mutations. ACS Chem Biol 11(10):2897–2907. https://doi.org/10.1021/acschembio.6b00480 Google Scholar
- 36.Young WB, Barbosa J, Blomgren P, Bremer MC, Crawford JJ, Dambach D, Eigenbrot C, Gallion S, Johnson AR, Kropf JE, Lee SH, Currie KS (2016) Discovery of highly potent and selective Bruton’s tyrosine kinase inhibitors: pyridazinone analogs with improved metabolic stability. Bioorg Med Chem Lett 26(2):575–579. https://doi.org/10.1016/j.bmcl.2015.11.076 Google Scholar
- 37.Young WB, Barbosa J, Blomgren P, Bremer MC, Crawford JJ, Dambach D, Gallion S, Hymowitz SG, Kropf JE, Lee SH, Liu L, Currie KS (2015) Potent and selective Bruton’s tyrosine kinase inhibitors: discovery of GDC-0834. Bioorg Med Chem Lett 25(6):1333–1337. https://doi.org/10.1016/j.bmcl.2015.01.032 Google Scholar
- 38.Wang X, Barbosa J, Blomgren P, Bremer MC, Chen J, Crawford JJ, Deng W, Dong L, Eigenbrot C, Gallion S, Hau J, Young WB (2017) Discovery of potent and selective tricyclic inhibitors of Bruton’s Tyrosine Kinase with improved druglike properties. ACS Med Chem Lett 8(6):608–613. https://doi.org/10.1021/acsmedchemlett.7b00103 Google Scholar
- 39.Crawford JJ, Johnson AR, Misner DL, Belmont LD, Castanedo G, Choy R, Coraggio M, Dong L, Eigenbrot C, Erickson R, Ghilardi N, Young WB (2018) Discovery of GDC-0853: a potent, selective, and noncovalent Bruton’s tyrosine kinase inhibitor in early clinical development. J Med Chem 61(6):2227–2245. https://doi.org/10.1021/acs.jmedchem.7b01712 Google Scholar
- 42.Bietz S, Inhester T, Lauck F, Sommer K, von Behren MM, Fährrolfes R, Flachsenberg F, Meyder A, Nittinger E, Otto T, Hilbig M, Rarey M (2017) From cheminformatics to structure-based design: web services and desktop applications based on the NAOMI library. J Biotechnol 261:207–214. https://doi.org/10.1016/j.jbiotec.2017.06.004 Google Scholar
- 45.WaterRank—Desert Scientific Software. http://www.desertsci.com/software-modules/waterrank/. Accessed 17 Sep 2017