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Journal Article

(R)-3-amidinophenylalanine-derived inhibitors of factor Xa with a novel active-site binding mode

MPS-Authors
http://pubman.mpdl.mpg.de/cone/persons/resource/persons78425

Mueller,  M. M.
Moroder, Luis / Bioorganic Chemistry, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78731

Sperl,  S.
Moroder, Luis / Bioorganic Chemistry, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons77772

Bode,  W.
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;
Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society;
Conti, Elena / Structural Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78419

Moroder,  L.
Moroder, Luis / Bioorganic Chemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Mueller, M. M., Sperl, S., Stürzebecher, J., Bode, W., & Moroder, L. (2002). (R)-3-amidinophenylalanine-derived inhibitors of factor Xa with a novel active-site binding mode. Biological Chemistry, 383(7-8), 1185-1191.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0010-6ED8-C
Abstract
A putative nonsubstrate like binding mode of (R)-3- amidinophenylalanine derivatives to factor Xa, as derived from modeling experiments based on Xray analysis of their complexes with trypsin, was used to design a new generation of inhibitors. However, the resulting inhibitory potencies were not at all consistent with the working assumption, although with an adamantylureido derivative of (R)-3- amidinophenylalanine phenetyl amide a highly selective nanomolar inhibition of factor Xa was achieved. The Xray analysis of the complex of this ligand with factor Xa revealed an unexpected new binding mode, of which the most important feature is the interaction of the Cterminal aryl moiety with a hydrophobic subregion of the S1 subsite, while the adamantyl group occupies the hydrophobic S3/S4 subsites of the enzyme.