Modeling loop backbone flexibility in receptor-ligand docking simulations
Copyright © 2012 Wiley Periodicals, Inc.
| Veröffentlicht in: | Journal of computational chemistry. - 1984. - 33(2012), 31 vom: 05. Dez., Seite 2504-15 |
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| Format: | Online-Aufsatz |
| Sprache: | English |
| Veröffentlicht: |
2012
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| Zugriff auf das übergeordnete Werk: | Journal of computational chemistry |
| Schlagworte: | Journal Article Ligands Protein Kinases EC 2.7.- Cyclic AMP-Dependent Protein Kinases EC 2.7.11.11 Mitogen-Activated Protein Kinase 1 EC 2.7.11.24 Mitogen-Activated Protein Kinase 14 |
| Zusammenfassung: | Copyright © 2012 Wiley Periodicals, Inc. The relevance of receptor conformational change during ligand binding is well documented for many pharmaceutically relevant receptors, but is still not fully accounted for in in silico docking methods. While there has been significant progress in treatment of receptor side chain flexibility sampling of backbone flexibility remains challenging because the conformational space expands dramatically and the scoring function must balance protein-protein and protein-ligand contributions. Here, we investigate an efficient multistage backbone reconstruction algorithm for large loop regions in the receptor and demonstrate that treatment of backbone receptor flexibility significantly improves binding mode prediction starting from apo structures and in cross docking simulations. For three different kinase receptors in which large flexible loops reconstruct upon ligand binding, we demonstrate that treatment of backbone flexibility results in accurate models of the complexes in simulations starting from the apo structure. At the example of the DFG-motif in the p38 kinase, we also show how loop reconstruction can be used to model allosteric binding. Our approach thus paves the way to treat the complex process of receptor reconstruction upon ligand binding in docking simulations and may help to design new ligands with high specificity by exploitation of allosteric mechanisms |
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| Beschreibung: | Date Completed 14.03.2013 Date Revised 19.10.2012 published: Print-Electronic Citation Status MEDLINE |
| ISSN: | 1096-987X |
| DOI: | 10.1002/jcc.23087 |