5LCE

Thrombin in complex with (S)-1-((R)-2-amino-3-cyclohexylpropanoyl)-N-(5-chloro-2-(hydroxymethyl)benzy l)pyrrolidine-2-carboxamide

5LCE の概要

• エントリーDOI: 10.2210/pdb5lce/pdb
• 分子名称: Prothrombin, GLYCEROL, Hirudin variant-2, ... (11 entities in total)
• 機能のキーワード: coagulation, blood clotting, convertion of fibrinogen to fibrin, blood clotting inhibitor, thrombin inhibitor, preorganization, glycosylation, blood, hydrolase
• 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: 36625.94

構造登録者

Sandner, A.,Heine, A.,Klebe, G. (登録日: 2016-06-21, 公開日: 2017-07-26, 最終更新日: 2024-11-20)

主引用文献

Sandner, A.,Hufner-Wulsdorf, T.,Heine, A.,Steinmetzer, T.,Klebe, G.
Strategies for Late-Stage Optimization: Profiling Thermodynamics by Preorganization and Salt Bridge Shielding.
J.Med.Chem., 62:9753-9771, 2019

PubMed Abstract: Structural fixation of a ligand in its bioactive conformation may, due to entropic reasons, improve affinity. We present a congeneric series of thrombin ligands with a variety of functional groups triggering preorganization prior to binding. Fixation in solution and complex formation have been characterized by crystallography, isothermal titration calorimetry (ITC), and molecular dynamics (MD) simulations. First, we show why these preorganizing modifications do not affect the overall binding mode and how key interactions are preserved. Next, we demonstrate how preorganization thermodynamics can be largely dominated by enthalpy rather than entropy because of the significant population of low-energy conformations. Furthermore, a salt bridge is shielded by actively reducing its surface exposure, thus leading to an enhanced enthalpic binding profile. Our results suggest that the consideration of the ligand solution ensemble by MD simulation is necessary to predict preorganizing modifications that enhance the binding behavior of already promising binders.

PubMed: 31633354
DOI: 10.1021/acs.jmedchem.9b01196

実験手法

X-RAY DIFFRACTION (1.39 Å)