Abstract Low-affinity ligands can be efficiently optimized into high-affinity drug leads by structure based drug design when atomic-resolution structural information on the protein/ligand complexes is available. In this work we show that the use of a few, easily obtainable, experimental restraints improves the accuracy of the docking experiments by two orders of magnitude. The experimental data are measured in nuclear magnetic resonance spectra and consist of protein-mediated NOEs between two competitively binding ligands. The methodology can be widely applied as the data are readily obtained for low-affinity ligands in the presence of non-labelled receptor at low concentration. The experimental inter-ligand NOEs are efficiently used to filter and rank complex model structures that have been pre-selected by docking protocols. This approach dramatically reduces the degeneracy and inaccuracy of the chosen model in docking experiments, is robust with respect to inaccuracy of the structural model used to represent the free receptor and is suitable for high-throughput docking campaigns.
Content Type Journal Article
Category Article
Pages 1-8
DOI 10.1007/s10858-011-9590-5
Authors
Julien Orts, EMBL, Structure and Computational Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany
Stefan Bartoschek, Sanofi-Aventis Deutschland GmbH, R&D LGCR/Parallel Synthesis & Natural Products, Industriepark Hoechst, Bldg. H811, 65926 Frankfurt am Main, Germany
Christian Griesinger, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany
Peter Monecke, Sanofi-Aventis Deutschland GmbH, R&D LGCR/Structure, Design & Informatics, Industriepark Hoechst, Bldg. G838, 65926 Frankfurt am Main, Germany
Teresa Carlomagno, EMBL, Structure and Computational Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany
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Application of NMR and Molecular Docking in Structure-Based Drug Discovery.
Application of NMR and Molecular Docking in Structure-Based Drug Discovery.
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Abstract
Drug discovery is a complex and costly endeavor, where few drugs that reach the clinical testing phase make it to market. High-throughput screening (HTS) is the primary method used by the pharmaceutical industry to identify initial lead compounds. Unfortunately, HTS has a high failure rate and is not particularly efficient at...
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Recently, we have developed a fast approach to calculate NMR chemical shifts using the divide and conquer method at the semiempirical level. To demonstrate the utility of this approach for characterizing protein-ligand interactions, we used the deviation of calculated chemical shift perturbations from experiment to determine the orientation of a ligand (GPI-1046) in the binding pocket of the FK506 binding...
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An NMR-based scoring function improves the accuracy of binding pose predictions by docking by two orders of magnitude
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