5AF9

Thrombin in complex with 4-Methoxy-N-(2-pyridinyl)benzamide

5AF9 の概要

• エントリーDOI: 10.2210/pdb5af9/pdb
• 分子名称: THROMBIN HEAVY CHAIN, 1,2-ETHANEDIOL, HIRUDIN VARIANT-2, ... (11 entities in total)
• 機能のキーワード: hydrolase, hydrolase inhibitor complex, serine protease, blood coagulation, blood clotting, convertion of fibrinogen to fibrin, blood clotting inhibitor, thrombin inhibitor, fragment, glycosylation, blood
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 35717.54

構造登録者

Ruehmann, E.,Heine, A.,Klebe, G. (登録日: 2015-01-20, 公開日: 2015-08-26, 最終更新日: 2024-11-06)

主引用文献

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

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: 26270568
DOI: 10.1021/ACS.JMEDCHEM.5B00812

実験手法

X-RAY DIFFRACTION (1.18 Å)