423768-50-7Relevant articles and documents
Molecular recognition at the active site of factor Xa: Cation-π Interactions, stacking on planar peptide surfaces, and replacement of structural water
Salonen, Laura M.,Holland, Mareike C.,Kaib, Philip S. J.,Haap, Wolfgang,Benz, J?rg,Mary, Jean-Luc,Kuster, Olivier,Schweizer, W. Bernd,Banner, David W.,Diederich, Fran?ois
supporting information; experimental part, p. 213 - 222 (2012/03/09)
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 cation-π 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. Structure-activity 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=2nM were obtained and their proposed binding geometries confirmed by X-ray co-crystal structures of protein-ligand complexes. Factor Xa is an ideal enzyme to undertake molecular recognition studies at atomic level resolution as its active site is completely conserved in complexes with designed ligands. Cation-π interactions, water replacements, and stacking interactions with flat peptide fragments were investigated, revealing large changes in binding affinity resulting from single-atom mutations or positional shifts of heteroatoms in the ligands. Copyright
