Probing the Subpockets of Factor Xa Reveals Two Binding Modes for Inhibitors Based on a 2-Carboxyindole Scaffold: A Study Combining Structure-Activity Relationship and X-ray Crystallography
| Autor: | Martin Lorenz, Michael Wagner, David William Will, Kurt Ritter, Melanie Essrich, Armin Bauer, Marc Nazaré, Volkmar Wehner, Volker Laux, Matthias Urmann, Hans Matter, Herman Schreuder, Jörg Czech |
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| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular Indole test Indoles Molecular model biology medicine.drug_mechanism_of_action Chemistry Stereochemistry Factor Xa Inhibitor Anticoagulants Plasma protein binding Crystallography X-Ray Ligand (biochemistry) Structure-Activity Relationship Enzyme inhibitor Factor Xa Drug Discovery Hydrolase biology.protein medicine Molecular Medicine Structure–activity relationship Factor Xa Inhibitors Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 48:4511-4525 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm0490540 |
| Popis: | Structure-activity relationships within a series of highly potent 2-carboxyindole-based factor Xa inhibitors incorporating a neutral P1 ligand are described with particular emphasis on the structural requirements for addressing subpockets of the factor Xa enzyme. Interactions with the subpockets were probed by systematic substitution of the 2-carboxyindole scaffold, in combination with privileged P1 and P4 substituents. Combining the most favorable substituents at the indole nucleus led to the discovery of a remarkably potent factor Xa inhibitor displaying a K(i) value of 0.07 nM. X-ray crystallography of inhibitors bound to factor Xa revealed substituent-dependent switching of the inhibitor binding mode and provided a rationale for the SAR obtained. These results underscore the key role played by the P1 ligand not only in determining the binding affinity of the inhibitor by direct interaction but also in modifying the binding mode of the whole scaffold, resulting in a nonlinear SAR. |
| Databáze: | OpenAIRE |
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