Combining in Silico and Biophysical Methods for the Development of Pseudomonas aeruginosa Quorum Sensing Inhibitors: An Alternative Approach for Structure-Based Drug Design
| Autor: | Michael P. Storz, Alberto Plaza, Rolf Müller, Matthias Groh, Christian Brengel, J. Henning Sahner, Rolf W. Hartmann |
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| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Drug In silico media_common.quotation_subject Carboxylic Acids Thiophenes Computational biology medicine.disease_cause Structure-Activity Relationship Cocrystallography Drug Discovery medicine Surface plasmon resonance media_common Dose-Response Relationship Drug Molecular Structure biology Pseudomonas aeruginosa Chemistry technology industry and agriculture Quorum Sensing Active site Isothermal titration calorimetry Quorum sensing Biochemistry Drug Design biology.protein Thermodynamics Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 56:8656-8664 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | The present work deals with the optimization of an inhibitor of PqsD, an enzyme essential for Pseudomonas aeruginosa quorum sensing apparatus. Molecular docking studies, supported by biophysical methods (surface plasmon resonance, isothermal titration calorimetry, saturation transfer difference NMR), were used to illuminate the binding mode of the 5-aryl-ureidothiophene-2-carboxylic acids. Enabled to make profound predictions, structure-based optimization led to increased inhibitory potency. Finally a covalent inhibitor was obtained. Binding to the active site was confirmed by LC-ESI-MS and MALDI-TOF-MS experiments. Following this rational approach, potent PqsD inhibitors were efficiently developed within a short period of time. This example shows that a combination and careful application of in silico and biophysical methods represents a powerful complement to cocrystallography. |
| Databáze: | OpenAIRE |
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