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Molecular Recognition at the Active Site of Factor Xa: Cation–π Interactions, Stacking on Planar Peptide Surfaces, and Replacement of Structural Water
Author(s) -
Salonen Laura M.,
Holland Mareike C.,
Kaib Philip S. J.,
Haap Wolfgang,
Benz Jörg,
Mary JeanLuc,
Kuster Olivier,
Schweizer W. Bernd,
Banner David W.,
Diederich François
Publication year - 2012
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201102571
Subject(s) - chemistry , stacking , active site , substituent , stereochemistry , crystallography , molecule , ligand (biochemistry) , binding site , peptide , enzyme , receptor , organic chemistry , biochemistry
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 K i =2 n M were obtained and their proposed binding geometries confirmed by X‐ray co‐crystal structures of protein–ligand complexes.