| Abstract
| - The design, synthesis, and structure−activity relationship of 3-oxybenzamides as potentinhibitors 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/inhibitorcomplexes led us to identify the major protein−ligand interactions. The binding mode ischaracterized by a lipophilic dichlorophenyl substituent interacting with Tyr228 in the proteaseS1 pocket, while polar parts are accommodated in S4. This alignment in combination withdocking allowed derivation of 3D-QSAR models and tailored scoring functions to rationalizebiological affinity and provide guidelines for optimization. The resulting models showed goodcorrelation coefficients and predictions of external test sets. Furthermore, they correspond tobinding site topologies in terms of steric, electrostatic, and hydrophobic complementarity. Twoapproaches to derive tailored scoring functions combining binding site and ligand informationled to predictive models with acceptable predictions of the external set. Good correlations toexperimental affinities were obtained for both AFMoC (adaptation of fields for molecularcomparison) and the novel TScore function. The SAR information from 3D-QSAR and tailoredscoring functions agrees with all experimental data and provides guidelines and reasonableactivity estimations for novel fXa inhibitors.
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