1kts

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[[Image:1kts.gif|left|200px]]
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{{Seed}}
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[[Image:1kts.png|left|200px]]
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{{STRUCTURE_1kts| PDB=1kts | SCENE= }}
{{STRUCTURE_1kts| PDB=1kts | SCENE= }}
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'''Thrombin Inhibitor Complex'''
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===Thrombin Inhibitor Complex===
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==Overview==
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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.
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The line below this paragraph, {{ABSTRACT_PUBMED_11960487}}, adds the Publication Abstract to the page
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(as it appears on PubMed at http://www.pubmed.gov), where 11960487 is the PubMed ID number.
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{{ABSTRACT_PUBMED_11960487}}
==About this Structure==
==About this Structure==
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[[Category: Blood coagulation]]
[[Category: Blood coagulation]]
[[Category: Inhibition]]
[[Category: Inhibition]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 23:09:51 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jul 2 10:59:22 2008''

Revision as of 07:59, 2 July 2008

Image:1kts.png

Template:STRUCTURE 1kts

Thrombin Inhibitor Complex

Template:ABSTRACT PUBMED 11960487

About this Structure

1KTS is a Protein complex structure of sequences from Hirudo medicinalis and Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structure-based design of novel potent nonpeptide thrombin inhibitors., Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W, J Med Chem. 2002 Apr 25;45(9):1757-66. PMID:11960487

Page seeded by OCA on Wed Jul 2 10:59:22 2008

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