title: (R)-3-Amidinophenylalanine-derived inhibitors of factor Xa with a novel active-site binding mode.
abstract: A putative non-substrate like binding mode of (R)-3-amidinophenylalanine derivatives to factor Xa, as derived from modeling experiments based on X-ray 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 adamantyl-ureido derivative of (R)-3-amidinophenylalanine phenetyl amide a highly selective nanomolar inhibition of factor Xa was achieved. The X-ray 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 C-terminal aryl moiety with a hydrophobic subregion of the S1 subsite, while the adamantyl group occupies the hydrophobic S3/S4 subsites of the enzyme.
authors.affiliation: Max-Planck-Institut für Biochemie, Martinsried, Germany.
authors.forename: Markus Michael
authors.initials: MM
authors.lastname: Mueller
authors.forename: Stefan
authors.initials: S
authors.lastname: Sperl
authors.forename: Jörg
authors.initials: J
authors.lastname: Stürzebecher
authors.forename: Wolfram
authors.initials: W
authors.lastname: Bode
authors.forename: Luis
authors.initials: L
authors.lastname: Moroder
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D010649:Phenylalanine; C020457:phenylalanine amide