Thrombin Inhibitors Identified by Computer-Assisted Multiparameter Design

Medientyp: E-Artikel
Titel: Thrombin Inhibitors Identified by Computer-Assisted Multiparameter Design
Beteiligte: Riester, Daniel; Wirsching, Frank; Salinas, Gabriela; Keller, Martina; Gebinoga, Michael; Kamphausen, Stefan; Merkwirth, Christian; Goetz, Ruediger; Wiesenfeldt, Martin; Stürzebecher, Jörg; Bode, Wolfram; Friedrich, Rainer; Thürk, Marcel; Schwienhorst, Andreas; Eigen, Manfred
Erschienen: National Academy of Sciences, 2005
Erschienen in: Proceedings of the National Academy of Sciences of the United States of America, 102 (2005) 24, Seite 8597-8602
Sprache: Englisch
ISSN: 0027-8424
Schlagwörter: Biological Sciences
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Beschreibung: 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.
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