Thrombin inhibitors identified by computer-assisted multiparameter design.
Here, we present a series of thrombin inhibitors that were generated by using powerful computer-assisted multiparameter optimization process. The process was organized in design cycles, starting with a set of randomly chosen molecules. Each cycle combined combinatorial synthesis, multiparameter characterization of compounds in a variety of bioassays, and algorithmic processing of the data to devise a set of compounds to be synthesized in the next cycle. The identified lead compounds exhibited thrombin inhibitory constants in the lower nanomolar range. They are by far the most selective synthetic thrombin inhibitors, with selectivities of >100,000-fold toward other proteases such as Factor Xa, Factor XIIa, urokinase, plasmin, and Plasma kallikrein. Furthermore, these compounds exhibit a favorable profile, comprising nontoxicity, high metabolic stability, low serum protein binding, good solubility, high anticoagulant activity, and a slow and exclusively renal elimination from the circulation in a rat model. Finally, x-ray crystallographic analysis of a thrombin-inhibitor complex revealed a binding mode with a neutral moiety in the S1 pocket of thrombin.
Riester
Daniel
D
Abteilung für Molekulare Genetik und Präparative Molekularbiologie, Institut für Mikrobiologie und Genetik, Grisebachstrasse 8, 37077 Göttingen, Germany.
Wirsching
Frank
F
Salinas
Gabriela
G
Keller
Martina
M
Gebinoga
Michael
M
Kamphausen
Stefan
S
Merkwirth
Christian
C
Goetz
Ruediger
R
Wiesenfeldt
Martin
M
Stürzebecher
Jörg
J
Bode
Wolfram
W
Friedrich
Rainer
R
Thürk
Marcel
M
Schwienhorst
Andreas
A
D000991:Antithrombins / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D017076:Computer-Aided Design; D003461:Crystallography; D015195:Drug Design; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis; D014361:Trypsin Inhibitors / Q000378:metabolism
D000991:Antithrombins; D010455:Peptides; D014361:Trypsin Inhibitors