1KTT: Thrombin Inhibitor Complex

Citation:
Abstract
The clinical syndromes of thromboembolism are evoked by an excessive stimulation of the coagulation cascade. In this context, the serine protease thrombin plays a key role. Considerable efforts have therefore been devoted to the discovery of safe, orally active inhibitors of this enzyme. On the basis of the X-ray crystal structure of the peptide-like thrombin inhibitor NAPAP complexed with bovine thrombin, we have designed a new structural class of nonpeptidic inhibitors employing a 1,2,5-trisubstituted benzimidazole as the central scaffold. Supported by a series of X-ray structure analyses, we optimized the activity of these compounds. Thrombin inhibition in the lower nanomolar range could be achieved although the binding energy mainly results from nonpolar, hydrophobic interactions. To improve in vivo potency, we increased the overall hydrophilicity of the molecules by introducing carboxylate groups. The very polar compound 24 (BIBR 953) exhibited the most favorable activity profile in vivo. This zwitterionic molecule was converted into the double-prodrug 31 (BIBR 1048), which showed strong oral activity in different animal species. On the basis of these results, 31 was chosen for clinical development.
PDB ID: 1KTTDownload
MMDB ID: 18432
PDB Deposition Date: 2002/1/17
Updated in MMDB: 2007/10
Experimental Method:
x-ray diffraction
Resolution: 2.1  Å
Source Organism:
Homo sapiens
Similar Structures:
Biological Unit for 1KTT: trimeric; determined by author and by software (PISA)
Molecular Components in 1KTT
Label Count Molecule
Proteins (3 molecules)
1
Thrombin(Gene symbol: F2)
Molecule annotation
1
Thrombin(Gene symbol: F2)
Molecule annotation
1
Hirudin IIB
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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