5JFD

Thrombin in complex with (S)-N-(2-(aminomethyl)-5-chlorobenzyl)-1-((benzylsulfonyl)-D-arginyl)pyrrolidine-2-carboxamide

Summary for 5JFD

• Entry DOI: 10.2210/pdb5jfd/pdb
• Related: 3EQ0
• Related PRD ID: PRD_000667
• Descriptor: Prothrombin, Hirudin variant-2, (2S)-N-[[2-(aminomethyl)-5-chloro-phenyl]methyl]-1-[(2R)-5-carbamimidamido-2-(phenylmethylsulfonylamino)pentanoyl]pyrrolidine-2-carboxamide, ... (9 entities in total)
• Functional Keywords: coagulation, blood clotting, convertion of fibrinogen to fibrin, blood clotting inhibitor, thrombin inhibitor, preorganization, glycosylation, blood, hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 36532.97

Authors

Sandner, A.,Heine, A.,Klebe, G. (deposition date: 2016-04-19, release date: 2017-05-24, Last modification date: 2024-01-10)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.46 Å)