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Ligand binding stepwise disrupts water network in thrombin: enthalpic and entropic changes reveal classical hydrophobic effect.

Biela A, Sielaff F, Terwesten F, Heine A, Steinmetzer T, Klebe G
J Med Chem 55 6094-110 (2012)
Related entries: 3rlw, 3rly, 3rm0, 3rml, 3rmm, 3rmn, 3rmo, 3t5f, 3uwj

Cited: 35 times
EuropePMC logo PMID: 22612268

Abstract

Well-ordered water molecules are displaced from thrombin's hydrophobic S3/4-pocket by P3-varied ligands (Gly, d-Ala, d-Val, d-Leu to d-Cha with increased hydrophobicity and steric requirement). Two series with 2-(aminomethyl)-5-chlorobenzylamide and 4-amidinobenzylamide at P1 were examined by ITC and crystallography. Although experiencing different interactions in S1, they display almost equal potency. For both scaffolds the terminal benzylsulfonyl substituent differs in binding, whereas the increasingly bulky P3-groups address S3/4 pocket similarly. Small substituents leave the solvation pattern unperturbed as found in the uncomplexed enzyme while increasingly larger ones stepwise displace the waters. Medium-sized groups show patterns with partially occupied waters. The overall 40-fold affinity enhancement correlates with water displacement and growing number of van der Waals contacts and is mainly attributed to favorable entropy. Both Gly derivatives deviate from the series and adopt different binding modes. Nonetheless, their thermodynamic signatures are virtually identical with the homologous d-Ala derivatives. Accordingly, unchanged thermodynamic profiles are no reliable indicator for conserved binding modes.

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  2. A benchmark driven guide to binding site comparison: An exhaustive evaluation using tailor-made data sets (ProSPECCTs). Ehrt C, Brinkjost T, Koch O. PLoS Comput Biol 14 e1006483 (2018)


Reviews citing this publication (11)

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  2. Applying thermodynamic profiling in lead finding and optimization. Klebe G. Nat Rev Drug Discov 14 95-110 (2015)
  3. The Molecular Origin of Enthalpy/Entropy Compensation in Biomolecular Recognition. Fox JM, Zhao M, Fink MJ, Kang K, Whitesides GM. Annu Rev Biophys 47 223-250 (2018)
  4. Water in protein hydration and ligand recognition. Maurer M, Oostenbrink C. J Mol Recognit 32 e2810 (2019)
  5. Thermodynamics of protein-ligand interactions as a reference for computational analysis: how to assess accuracy, reliability and relevance of experimental data. Krimmer SG, Klebe G. J Comput Aided Mol Des 29 867-883 (2015)
  6. Applications of isothermal titration calorimetry - the research and technical developments from 2011 to 2015. Falconer RJ. J Mol Recognit 29 504-515 (2016)
  7. Size does matter! Label-free detection of small molecule-protein interaction. Fechner P, Bleher O, Ewald M, Freudenberger K, Furin D, Hilbig U, Kolarov F, Krieg K, Leidner L, Markovic G, Proll G, Pröll F, Rau S, Riedt J, Schwarz B, Weber P, Widmaier J. Anal Bioanal Chem 406 4033-4051 (2014)
  8. Structural Biology of HIV Integrase Strand Transfer Inhibitors. Jóźwik IK, Passos DO, Lyumkis D. Trends Pharmacol Sci 41 611-626 (2020)
  9. Redesign of water networks for efficient biocatalysis. Fink MJ, Syrén PO. Curr Opin Chem Biol 37 107-114 (2017)
  10. Enzyme inhibition as a potential therapeutic strategy to treat COVID-19 infection. Paulsson-Habegger L, Snabaitis AK, Wren SP. Bioorg Med Chem 48 116389 (2021)
  11. Forces Driving a Magic Bullet to Its Target: Revisiting the Role of Thermodynamics in Drug Design, Development, and Optimization. Minetti CA, Remeta DP. Life (Basel) 12 1438 (2022)

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  1. The hydrophobic effect revisited--studies with supramolecular complexes imply high-energy water as a noncovalent driving force. Biedermann F, Nau WM, Schneider HJ. Angew Chem Int Ed Engl 53 11158-11171 (2014)
  2. Identification of the first synthetic inhibitors of the type II transmembrane serine protease TMPRSS2 suitable for inhibition of influenza virus activation. Meyer D, Sielaff F, Hammami M, Böttcher-Friebertshäuser E, Garten W, Steinmetzer T. Biochem J 452 331-343 (2013)
  3. Dissecting the hydrophobic effect on the molecular level: the role of water, enthalpy, and entropy in ligand binding to thermolysin. Biela A, Nasief NN, Betz M, Heine A, Hangauer D, Klebe G. Angew Chem Int Ed Engl 52 1822-1828 (2013)
  4. Methyl, ethyl, propyl, butyl: futile but not for water, as the correlation of structure and thermodynamic signature shows in a congeneric series of thermolysin inhibitors. Krimmer SG, Betz M, Heine A, Klebe G. ChemMedChem 9 833-846 (2014)
  5. Development and characterization of new peptidomimetic inhibitors of the West Nile virus NS2B-NS3 protease. Hammamy MZ, Haase C, Hammami M, Hilgenfeld R, Steinmetzer T. ChemMedChem 8 231-241 (2013)
  6. Biomacromolecular quantitative structure-activity relationship (BioQSAR): a proof-of-concept study on the modeling, prediction and interpretation of protein-protein binding affinity. Zhou P, Wang C, Tian F, Ren Y, Yang C, Huang J. J Comput Aided Mol Des 27 67-78 (2013)
  7. Replica-Exchange and Standard State Binding Free Energies with Grand Canonical Monte Carlo. Ross GA, Bruce Macdonald HE, Cave-Ayland C, Cabedo Martinez AI, Essex JW. J Chem Theory Comput 13 6373-6381 (2017)
  8. 2D IR spectroscopy reveals the role of water in the binding of channel-blocking drugs to the influenza M2 channel. Ghosh A, Wang J, Moroz YS, Korendovych IV, Zanni M, DeGrado WF, Gai F, Hochstrasser RM. J Chem Phys 140 235105 (2014)
  9. Allosteric Inhibition of Factor XIIIa. Non-Saccharide Glycosaminoglycan Mimetics, but Not Glycosaminoglycans, Exhibit Promising Inhibition Profile. Al-Horani RA, Karuturi R, Lee M, Afosah DK, Desai UR. PLoS One 11 e0160189 (2016)
  10. Water-Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase. Fox JM, Kang K, Sastry M, Sherman W, Sankaran B, Zwart PH, Whitesides GM. Angew Chem Int Ed Engl 56 3833-3837 (2017)
  11. Solvent effects on ligand binding to a serine protease. Gopal SM, Klumpers F, Herrmann C, Schäfer LV. Phys Chem Chem Phys 19 10753-10766 (2017)
  12. Bacterial protease uses distinct thermodynamic signatures for substrate recognition. Bezerra GA, Ohara-Nemoto Y, Cornaciu I, Fedosyuk S, Hoffmann G, Round A, Márquez JA, Nemoto TK, Djinović-Carugo K. Sci Rep 7 2848 (2017)
  13. Flooding enzymes: quantifying the contributions of interstitial water and cavity shape to ligand binding using extended linear response free energy calculations. Whalen KL, Spies MA. J Chem Inf Model 53 2349-2359 (2013)
  14. Water Networks Repopulate Protein-Ligand Interfaces with Temperature. Stachowski TR, Vanarotti M, Seetharaman J, Lopez K, Fischer M. Angew Chem Int Ed Engl 61 e202112919 (2022)
  15. Boosting Affinity by Correct Ligand Preorganization for the S2 Pocket of Thrombin: A Study by Isothermal Titration Calorimetry, Molecular Dynamics, and High-Resolution Crystal Structures. Rühmann EH, Rupp M, Betz M, Heine A, Klebe G. ChemMedChem 11 309-319 (2016)
  16. Entropic and enthalpic contributions to stereospecific ligand binding from enhanced sampling methods. Lai B, Nagy G, Garate JA, Oostenbrink C. J Chem Inf Model 54 151-158 (2014)
  17. The impact of introducing a histidine into an apolar cavity site on docking and ligand recognition. Merski M, Shoichet BK. J Med Chem 56 2874-2884 (2013)
  18. Retroviral integrase: Structure, mechanism, and inhibition. Passos DO, Li M, Craigie R, Lyumkis D. Enzymes 50 249-300 (2021)
  19. Thrombin-Inhibiting Anticoagulant Liposomes: Development and Characterization. Endreas W, Brüßler J, Vornicescu D, Keusgen M, Bakowsky U, Steinmetzer T. ChemMedChem 11 340-349 (2016)
  20. Conserved Water Networks Identification for Drug Design Using Density Clustering Approaches on Positional and Orientational Data. Tošović J, Fijan D, Jukič M, Bren U. J Chem Inf Model 62 6105-6117 (2022)
  21. Changing the selectivity profile - from substrate analog inhibitors of thrombin and factor Xa to potent matriptase inhibitors. Maiwald A, Hammami M, Wagner S, Heine A, Klebe G, Steinmetzer T. J Enzyme Inhib Med Chem 31 89-97 (2016)
  22. Interaction of the synthetic antithrombotic peptide P10 with thrombin: a spectroscopy study. Chen F, Jiang H, Chen W, Huang G. RSC Adv 9 18498-18505 (2019)


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