Molecular Recognition at the Active Site of Factor Xa: Cation-p Interactions, Stacking on Planar Peptide Surfaces, and Replacement of Structural Water

Factor Xa, a serine protease from the blood coagulation cascade, is an ideal enzyme for molecular recognition studies, as its active site is highly shape-persistent and features distinct, concave sub-pockets. We developed a family of non-peptidic, small-molecule inhibitors with a central tricyclic c...

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Bibliographic Details
Published inChemistry : a European journal Vol. 18; no. 1; pp. 213 - 222
Main Authors Salonen, Laura M., Holland, Mareike C., Kaib, Philip S. J., Haap, Wolfgang, Benz, Joerg, Mary, Jean-Luc, Kuster, Olivier, Schweizer, W. Bernd, Banner, David W., Diederich, Francois
Format Journal Article
LanguageEnglish
Published WEINHEIM Wiley 01.01.2012
Subjects
Chemistry
Chemistry, Multidisciplinary
Physical Sciences
Science & Technology
DESIGN
TETRAMETHYLAMMONIUM
THROMBIN
CRYSTAL-STRUCTURE
AROMATIC RINGS
cation-p interactions
2-CARBOXYINDOLE SCAFFOLD
DISCOVERY
ligand conformations
molecular recognition
factor Xa
INHIBITORS
enzyme inhibitors
RECEPTORS
BINDING
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Summary:Factor Xa, a serine protease from the blood coagulation cascade, is an ideal enzyme for molecular recognition studies, as its active site is highly shape-persistent and features distinct, concave sub-pockets. We developed a family of non-peptidic, small-molecule inhibitors with a central tricyclic core orienting a neutral heterocyclic substituent into the S1 pocket and a quaternary ammonium ion into the aromatic box in the S4 pocket. The substituents were systematically varied to investigate cationp interactions in the S4 pocket, optimal heterocyclic stacking on the flat peptide walls lining the S1 pocket, and potential water replacements in both the S1 and the S4 pockets. Structureactivity relationships were established to reveal and quantify contributions to the binding free enthalpy, resulting from single-atom replacements or positional changes in the ligands. A series of high-affinity ligands with inhibitory constants down to Ki=2 nM were obtained and their proposed binding geometries confirmed by X-ray co-crystal structures of proteinligand complexes.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201102571