title: Structural requirements for factor Xa inhibition by 3-oxybenzamides with neutral P1 substituents: combining X-ray crystallography, 3D-QSAR, and tailored scoring functions.
abstract: The design, synthesis, and structure-activity relationship of 3-oxybenzamides as potent inhibitors of the coagulation protease factor Xa are described on the basis of X-ray structures, privileged structure motifs, and SAR information. A total of six X-ray structures of fXa/inhibitor complexes led us to identify the major protein-ligand interactions. The binding mode is characterized by a lipophilic dichlorophenyl substituent interacting with Tyr228 in the protease S1 pocket, while polar parts are accommodated in S4. This alignment in combination with docking allowed derivation of 3D-QSAR models and tailored scoring functions to rationalize biological affinity and provide guidelines for optimization. The resulting models showed good correlation coefficients and predictions of external test sets. Furthermore, they correspond to binding site topologies in terms of steric, electrostatic, and hydrophobic complementarity. Two approaches to derive tailored scoring functions combining binding site and ligand information led to predictive models with acceptable predictions of the external set. Good correlations to experimental affinities were obtained for both AFMoC (adaptation of fields for molecular comparison) and the novel TScore function. The SAR information from 3D-QSAR and tailored scoring functions agrees with all experimental data and provides guidelines and reasonable activity estimations for novel fXa inhibitors.
authors.affiliation: DI and A Chemistry, Aventis Pharma Deutschland GmbH, A Company of the Sanofi-Aventis Group, Building G 878, D-65926 Frankfurt am Main, Germany. hans.matter@aventis.com
authors.forename: Hans
authors.initials: H
authors.lastname: Matter
authors.forename: David W
authors.initials: DW
authors.lastname: Will
authors.forename: Marc
authors.initials: M
authors.lastname: Nazaré
authors.forename: Herman
authors.initials: H
authors.lastname: Schreuder
authors.forename: Volker
authors.initials: V
authors.lastname: Laux
authors.forename: Volkmar
authors.initials: V
authors.lastname: Wehner
mesh_terms: D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015951:Factor Xa / Q000737:chemistry*; D065427:Factor Xa Inhibitors; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D001549:Benzamides; D065427:Factor Xa Inhibitors; D008024:Ligands; D013917:Thrombin; D015951:Factor Xa