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

Nittinger E, Gibbons P, Eigenbrot C, Davies DR, Maurer B, Yu CL, Kiefer JR, Kuglstatter A, Murray J, Ortwine DF, Tang Y, Tsui V
J Comput Aided Mol Des 33 307-330 (2019)
Related entries: 6bik, 6bke, 6bkh, 6bkw, 6bqa, 6bqd, 6ep9

Cited: 13 times
EuropePMC logo PMID: 30756207

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.

Articles - 6bln mentioned but not cited (1)

  1. Ligand binding: evaluating the contribution of the water molecules network using the Fragment Molecular Orbital method. Lukac I, Wyatt PG, Gilbert IH, Zuccotto F. J Comput Aided Mol Des 35 1025-1036 (2021)


Reviews citing this publication (2)

  1. Recent PELE Developments and Applications in Drug Discovery Campaigns. Puch-Giner I, Molina A, Municoy M, Pérez C, Guallar V. Int J Mol Sci 23 16090 (2022)
  2. The Advances and Limitations of the Determination and Applications of Water Structure in Molecular Engineering. Zsidó BZ, Bayarsaikhan B, Börzsei R, Szél V, Mohos V, Hetényi C. Int J Mol Sci 24 11784 (2023)

Articles citing this publication (10)

  1. Efficient consideration of coordinated water molecules improves computational protein-protein and protein-ligand docking discrimination. Pavlovicz RE, Park H, DiMaio F. PLoS Comput Biol 16 e1008103 (2020)
  2. Biotransformation: Impact and Application of Metabolism in Drug Discovery. Shanu-Wilson J, Evans L, Wrigley S, Steele J, Atherton J, Boer J. ACS Med Chem Lett 11 2087-2107 (2020)
  3. A Molecular Dynamics Study of Vasoactive Intestinal Peptide Receptor 1 and the Basis of Its Therapeutic Antagonism. Latek D, Langer I, Krzysko K, Charzewski L. Int J Mol Sci 20 (2019)
  4. Binding selectivity of inhibitors toward the first over the second bromodomain of BRD4: theoretical insights from free energy calculations and multiple short molecular dynamics simulations. Wang Y, Wu S, Wang L, Yang Z, Zhao J, Zhang L. RSC Adv 11 745-759 (2020)
  5. De novo prediction of explicit water molecule positions by a novel algorithm within the protein design software MUMBO. Kriegel M, Muller YA. Sci Rep 13 16680 (2023)
  6. In Silico Evaluation of the Thr58-Associated Conserved Water with KRAS Switch-II Pocket Binders. Leini R, Pantsar T. J Chem Inf Model 63 1490-1505 (2023)
  7. TWN-FS method: A novel fragment screening method for drug discovery. Yoon HR, Park GJ, Balupuri A, Kang NS. Comput Struct Biotechnol J 21 4683-4696 (2023)
  8. Utilizing Grand Canonical Monte Carlo Methods in Drug Discovery. Bodnarchuk MS, Packer MJ, Haywood A. ACS Med Chem Lett 11 77-82 (2020)
  9. Water Thermodynamics of Peptide Toxin Binding Sites on Ion Channels. Shah B, Sindhikara D, Borrelli K, Leffler AE. Toxins (Basel) 12 (2020)
  10. WaterKit: Thermodynamic Profiling of Protein Hydration Sites. Eberhardt J, Forli S. J Chem Theory Comput 19 2535-2556 (2023)


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