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Fragment Binding Can Be Either More Enthalpy-Driven or Entropy-Driven: Crystal Structures and Residual Hydration Patterns Suggest Why.

Rühmann E, Betz M, Heine A, Klebe G
J Med Chem 58 6960-71 (2015)
Related entries: 4ud9, 4udw, 4ue7, 4ueh, 5afy, 5afz, 5ahg

Cited: 15 times
EuropePMC logo PMID: 26270568

Abstract

In lead optimization, small, enthalpically advantaged fragments have been suggested to be superior, as an entropic component will be added inevitably during late-stage optimization. Determination of thermodynamic signatures of weak-binding fragments is essential to support the decision-making process, to decide which fragment to take to further optimization. High-resolution crystal structures of six fragments binding to the S1 pocket of thrombin were determined and analyzed with respect to their thermodynamic profile. The two most potent fragments exhibiting an amidine-type scaffold are not the most enthalpic binders; instead a chloro-thiophene fragment binds more enthalpically. Two chemically very similar chloro-aromatic fragments differ strongly in their potency (430 μM vs 10 mM); their binding modes are related, but the surrounding residual water network differs. The more potent one recruits a water molecule and involves Glu192 in binding, thus succeeding in firmly capping the S1 pocket. Fragments exhibiting a rather perfect solvation pattern in their binding mode also experience the highest potency.

Reviews citing this publication (3)

  1. 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)
  2. The History of mARC. Clement B, Struwe MA. Molecules 28 4713 (2023)
  3. 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)

Articles citing this publication (12)

  1. Is It Reliable to Take the Molecular Docking Top Scoring Position as the Best Solution without Considering Available Structural Data? Ramírez D, Caballero J. Molecules 23 E1038 (2018)
  2. Intriguing role of water in protein-ligand binding studied by neutron crystallography on trypsin complexes. Schiebel J, Gaspari R, Wulsdorf T, Ngo K, Sohn C, Schrader TE, Cavalli A, Ostermann A, Heine A, Klebe G. Nat Commun 9 3559 (2018)
  3. Fragment Hits: What do They Look Like and How do They Bind? Giordanetto F, Jin C, Willmore L, Feher M, Shaw DE. J Med Chem 62 3381-3394 (2019)
  4. Application of ITC-Based Characterization of Thermodynamic and Kinetic Association of Ligands With Proteins in Drug Design. Su H, Xu Y. Front Pharmacol 9 1133 (2018)
  5. Lead Identification of 8-(Methylamino)-2-oxo-1,2-dihydroquinoline Derivatives as DNA Gyrase Inhibitors: Hit-to-Lead Generation Involving Thermodynamic Evaluation. Ushiyama F, Amada H, Takeuchi T, Tanaka-Yamamoto N, Kanazawa H, Nakano K, Mima M, Masuko A, Takata I, Hitaka K, Iwamoto K, Sugiyama H, Ohtake N. ACS Omega 5 10145-10159 (2020)
  6. Uncertainty in protein-ligand binding constants: asymmetric confidence intervals versus standard errors. Paketurytė V, Petrauskas V, Zubrienė A, Abian O, Bastos M, Chen WY, Moreno MJ, Krainer G, Linkuvienė V, Sedivy A, Velazquez-Campoy A, Williams MA, Matulis D. Eur Biophys J 50 661-670 (2021)
  7. Intrinsic Thermodynamics and Structures of 2,4- and 3,4-Substituted Fluorinated Benzenesulfonamides Binding to Carbonic Anhydrases. Zubrienė A, Smirnov A, Dudutienė V, Timm DD, Matulienė J, Michailovienė V, Zakšauskas A, Manakova E, Gražulis S, Matulis D. ChemMedChem 12 161-176 (2017)
  8. Combining molecular dynamics simulation and ligand-receptor contacts analysis as a new approach for pharmacophore modeling: beta-secretase 1 and check point kinase 1 as case studies. Hatmal MM, Jaber S, Taha MO. J Comput Aided Mol Des 30 1149-1163 (2016)
  9. 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)
  10. Synthesis and Solution-Phase Characterization of Sulfonated Oligothioetheramides. Brown JS, Acevedo YM, He GD, Freed JH, Clancy P, Alabi CA. Macromolecules 50 8731-8738 (2017)
  11. Partial filling affinity capillary electrophoresis as a useful tool for fragment-based drug discovery: A proof of concept on thrombin. Farcaş E, Bouckaert C, Servais AC, Hanson J, Pochet L, Fillet M. Anal Chim Acta 984 211-222 (2017)
  12. Exploiting activity cliffs for building pharmacophore models and comparison with other pharmacophore generation methods: sphingosine kinase 1 as case study. Mousa LA, Hatmal MM, Taha M. J Comput Aided Mol Des 36 39-62 (2022)


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