5AF9
Thrombin in complex with 4-Methoxy-N-(2-pyridinyl)benzamide
Summary for 5AF9
| Entry DOI | 10.2210/pdb5af9/pdb |
| Descriptor | THROMBIN HEAVY CHAIN, 1,2-ETHANEDIOL, HIRUDIN VARIANT-2, ... (11 entities in total) |
| Functional Keywords | hydrolase, hydrolase inhibitor complex, serine protease, blood coagulation, blood clotting, convertion of fibrinogen to fibrin, blood clotting inhibitor, thrombin inhibitor, fragment, glycosylation, blood |
| Biological source | HOMO SAPIENS (HUMAN) More |
| Total number of polymer chains | 3 |
| Total formula weight | 35717.54 |
| Authors | Ruehmann, E.,Heine, A.,Klebe, G. (deposition date: 2015-01-20, release date: 2015-08-26, Last modification date: 2024-11-06) |
| Primary citation | Ruehmann, E.,Betz, M.,Heine, A.,Klebe, G. Fragments Can Bind Either More Enthalpy or Entropy-Driven: Crystal Structures and Residual Hydration Pattern Suggest Why. J.Med.Chem., 58:6960-, 2015 Cited by PubMed 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. PubMed: 26270568DOI: 10.1021/ACS.JMEDCHEM.5B00812 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.18 Å) |
Structure validation
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