1KTS

Thrombin Inhibitor Complex

Summary for 1KTS

• Entry DOI: 10.2210/pdb1kts/pdb
• Related: 1G30 1G32 1KTT
• Descriptor: thrombin, hirudin IIB, 3-({2-[(4-CARBAMIMIDOYL-PHENYLAMINO)-METHYL]-3-METHYL-3H-BENZOIMIDAZOLE-5-CARBONYL}-PYRIDIN-2-YL-AMINO)-PROPIONIC ACID ETHYL ESTER, ... (5 entities in total)
• Functional Keywords: blood coagulation, inhibition, blood clotting, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted, extracellular space: P00734 P00734; Secreted: P28506
• Total number of polymer chains: 3
• Total formula weight: 35867.84

Authors

Nar, H. (deposition date: 2002-01-17, release date: 2002-02-06, Last modification date: 2024-11-20)

Primary citation

Hauel, N.H.,Nar, H.,Priepke, H.,Ries, U.,Stassen, J.M.,Wienen, W.
Structure-based design of novel potent nonpeptide thrombin inhibitors.
J.Med.Chem., 45:1757-1766, 2002

PubMed 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.

PubMed: 11960487
DOI: 10.1021/jm0109513

Experimental method

X-RAY DIFFRACTION (2.4 Å)