Selective boron-Containing thrombin inhibitors—X-ray analysis reveals surprising binding mode

• Published in: Bioorganic & medicinal chemistry Vol. 8; no. 9; pp. 2291 - 2303
• Main Authors: von Matt, Anette, Ehrhardt, Claus, Burkhard, Peter, Metternich, Rainer, Walkinshaw, Malcolm, Tapparelli, Carlo
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-09-2000; Elsevier Science
• Subjects: Amides - chemical synthesis; Amides - chemistry; Binding Sites; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Boronic Acids - chemical synthesis; Boronic Acids - chemistry; Boronic Acids - metabolism; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Fibrinolysin - metabolism; Fibrinolytic Agents - chemical synthesis; Fibrinolytic Agents - chemistry; Fibrinolytic Agents - metabolism; Humans; Kinetics; Ligands; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Protein Binding; Structure-Activity Relationship; Terpenes - chemical synthesis; Terpenes - chemistry; Thrombin - antagonists & inhibitors; Trypsin - metabolism; Urea - chemical synthesis; Urea - chemistry; Serine endopeptidases; Peptides; Enzyme; Silicon Organic compounds; Enzyme inhibitor; Thrombin; Modeling; Peptidases; Structure activity relation; Molecular model; Dipeptides; Binding mode; Hydrolases; Boron Organic compounds; Chemical synthesis; Boronic acids
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(00)00147-4

Based on the structural comparison of the S1 pocket in different trypsin-like serine proteases, a series of Boc-
d-trimethylsilylalanine-proline-boro-X pinanediol derivatives, with boro-X being different amino boronic acids, have been synthesized as inhibitors of thrombin. Among the novel compounds, a number of derivatives were synthesized which appeared to have side-chain variants too big to fit into the S1 pocket. Nevertheless, these compounds inhibited thrombin in the nM range. The X-ray structure of one of these inhibitors bound to the active side of thrombin reveals that a new binding mode is responsible for these surprising results.