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

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.

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Genre: Journal Article
Alternative Title : Biol. Chem.

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 Creators:
Mueller, M. M.1, Author           
Sperl, S.1, Author           
Stürzebecher, J.2, Author           
Bode, W.3, 4, 5, Author           
Moroder, L.1, Author           
Affiliations:
1Moroder, Luis / Bioorganic Chemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565160              
2External Organizations, ou_persistent22              
3Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565147              
4Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565155              
5Conti, Elena / Structural Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565144              

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Free keywords: (R)-3-amidinophenylalanine; factor Xa; novel active-site binding mode; S1 subregion; synthetic inhibitors; X-ray crystal structure
 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.

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Language(s): eng - English
 Dates: 2002-07
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 35077
ISI: 000177737800021
 Degree: -

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Title: Biological Chemistry
  Alternative Title : Biol. Chem.
Source Genre: Journal
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Publ. Info: -
Pages: - Volume / Issue: 383 (7-8) Sequence Number: - Start / End Page: 1185 - 1191 Identifier: ISSN: 1431-6730