1BHX

X-RAY STRUCTURE OF THE COMPLEX OF HUMAN ALPHA THROMBIN WITH THE INHIBITOR SDZ 229-357

Summary for 1BHX

• Entry DOI: 10.2210/pdb1bhx/pdb
• Descriptor: ALPHA THROMBIN, 5-OXO-6-PHENYLMETHANESULFONYLAMINO-HEXAHYDRO-THIAZOLO[3,2-A]PYRIDINE-3-CARBOXYLIC ACID (3-GUANIDINO-PROPYL)-AMIDE, ... (6 entities in total)
• Functional Keywords: serine protease
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted, extracellular space: P00734 P00734 P00734
• Total number of polymer chains: 4
• Total formula weight: 33622.49

Authors

Kallen, J. (deposition date: 1998-06-10, release date: 1998-11-04, Last modification date: 2024-11-13)

Primary citation

Wagner, J.,Kallen, J.,Ehrhardt, C.,Evenou, J.P.,Wagner, D.
Rational design, synthesis, and X-ray structure of selective noncovalent thrombin inhibitors.
J.Med.Chem., 41:3664-3674, 1998

PubMed Abstract: We have designed, synthesized, and tested in vitro a novel class of noncovalent thrombin inhibitors. The main feature of these inhibitors is a 6,5-fused bicyclic core structure that fills the S2 pocket of the active site of thrombin. The bicycle introduces conformational constraint into the ligand and locks the Xaa-Pro amide bond into the desired trans configuration. Among the known ring systems, we selected by molecular modeling the 7-thiaindolizidinones (BTD) as our basic template. The influence of several structural features was analyzed: the length of the argininal side chain, the stereochemistry at C6, and the importance of making optimal use of the S3 pocket. Finally, an X-ray crystal structure of inhibitor 15 bound to thrombin was obtained at a resolution of 2.3 A. These designed thrombin inhibitors, which were prepared by an efficient synthesis, showed high selectivity over trypsin and other serine proteases. Further derivation based on the information obtained by X-ray crystallography should certainly allow to improve the potency.

PubMed: 9733491
DOI: 10.1021/jm981013e

Experimental method

X-RAY DIFFRACTION (2.3 Å)