title: Thrombin inhibitors identified by computer-assisted multiparameter design.
abstract: 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.
authors.affiliation: Abteilung für Molekulare Genetik und Präparative Molekularbiologie, Institut für Mikrobiologie und Genetik, Grisebachstrasse 8, 37077 Göttingen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Riester
authors.forename: Frank
authors.initials: F
authors.lastname: Wirsching
authors.forename: Gabriela
authors.initials: G
authors.lastname: Salinas
authors.forename: Martina
authors.initials: M
authors.lastname: Keller
authors.forename: Michael
authors.initials: M
authors.lastname: Gebinoga
authors.forename: Stefan
authors.initials: S
authors.lastname: Kamphausen
authors.forename: Christian
authors.initials: C
authors.lastname: Merkwirth
authors.forename: Ruediger
authors.initials: R
authors.lastname: Goetz
authors.forename: Martin
authors.initials: M
authors.lastname: Wiesenfeldt
authors.forename: Jörg
authors.initials: J
authors.lastname: Stürzebecher
authors.forename: Wolfram
authors.initials: W
authors.lastname: Bode
authors.forename: Rainer
authors.initials: R
authors.lastname: Friedrich
authors.forename: Marcel
authors.initials: M
authors.lastname: Thürk
authors.forename: Andreas
authors.initials: A
authors.lastname: Schwienhorst
mesh_terms: 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
chemical_list: D000991:Antithrombins; D010455:Peptides; D014361:Trypsin Inhibitors