Selective boron-containing thrombin inhibitors--X-ray analysis reveals surprising binding mode.
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.
von Matt
A
A
Novartis Pharma AG, Basel, Switzerland. anette.von_matt@pharma.novartis.com
Ehrhardt
C
C
Burkhard
P
P
Metternich
R
R
Walkinshaw
M
M
Tapparelli
C
C
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry; D000081008:Bicyclic Monoterpenes; D001665:Binding Sites; D001897:Boronic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000138:chemical synthesis / Q000737:chemistry; D013917:Thrombin / Q000037:antagonists & inhibitors*; D014357:Trypsin / Q000378:metabolism; D014508:Urea / Q000138:chemical synthesis / Q000737:chemistry
D000577:Amides; D000081008:Bicyclic Monoterpenes; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; D008024:Ligands; D013729:Terpenes; C030216:pinane; D014508:Urea; D014357:Trypsin; D013917:Thrombin; D005341:Fibrinolysin