1KTT

Thrombin inhibitor complex

1KTT の概要

• エントリーDOI: 10.2210/pdb1ktt/pdb
• 関連するPDBエントリー: 1G30 1G32 1KTs
• 分子名称: thrombin, hirudin IIB, 4-(5-BENZENESULFONYLAMINO-1-METHYL-1H-BENZOIMIDAZOL-2-YLMETHYL)-BENZAMIDINE, ... (5 entities in total)
• 機能のキーワード: blood coagulation, inhibition, blood clotting, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Secreted, extracellular space: P00734 P00734; Secreted: P28506
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 35787.78

構造登録者

Nar, H. (登録日: 2002-01-17, 公開日: 2002-02-06, 最終更新日: 2024-10-30)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.1 Å)