3PO1

Thrombin in complex with Benzothiazole Guanidine

Summary for 3PO1

• Entry DOI: 10.2210/pdb3po1/pdb
• Descriptor: Thrombin light chain, Thrombin heavy chain, thrombin peptide, ... (8 entities in total)
• Functional Keywords: serine protease, coagulation factor ii, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted, extracellular space: P00734 P00734 P00734
• Total number of polymer chains: 4
• Total formula weight: 33563.35

Authors

Xue, Y. (deposition date: 2010-11-21, release date: 2011-11-23, Last modification date: 2024-11-20)

Primary citation

Karle, M.,Knecht, W.,Xue, Y.
Discovery of benzothiazole guanidines as novel inhibitors of thrombin and trypsin IV.
Bioorg.Med.Chem.Lett., 22:4839-4843, 2012

PubMed Abstract: In a project to find novel neutral P1 fragments for the synthesis of thrombin inhibitors with improved pharmacokinetic properties, fragments containing a benzothiazole guanidine scaffold were identified as weak thrombin inhibitors. WaterLOGSY (Water-Ligand Observed via Gradient SpectroscopY) NMR was used to detect fragments binding to thrombin and these fragments were followed up by Biacore A100 affinity measurements and enzyme assays. A crystal structure of the most potent compound with thrombin was obtained and revealed an unexpected binding mode as well as the key interactions of the fragment with the protein. Based on these results, the structure-based design and synthesis of a small series of optimized novel substituted benzothiazole guanidines with comparatively low pK(a) values was accomplished. Testing of these compounds against human trypsin I and human trypsin IV revealed unexpected inhibitory activity and selectivity of some of the compounds, making them attractive starting points for selective trypsin inhibitors.

PubMed: 22726924
DOI: 10.1016/j.bmcl.2012.05.046

Experimental method

X-RAY DIFFRACTION (1.65 Å)