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        Flexible Ligand Docking with Glide

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        1381
        • Abstract
        • Table of Contents
        • Figures
        • Literature Cited

        Abstract

         

        Glide is a ligand docking program for predicting protein?ligand binding modes and ranking ligands via high?throughput virtual screening. Glide utilizes two different scoring functions, SP and XP GlideScore, to rank?order compounds. Three modes of sampling ligand conformational and positional degrees of freedom are available to determine the optimal ligand orientation relative to a rigid protein receptor geometry. This unit presents protocols for flexible ligand docking with Glide, optionally including ligand constraints or ligand molecular similarities.

        Keywords: ligand docking; protein?ligand interactions; protein?ligand binding

             
         
        GO TO THE FULL PROTOCOL:
        PDF or HTML at Wiley Online Library

        Table of Contents

        • Strategic Planning
        • Basic Protocol 1: Grid Generation
        • Basic Protocol 2: Flexible Ligand Docking
        • Alternate Protocol 1: Grid Generation with Constraints
        • Alternate Protocol 2: Flexible Ligand Docking with Constraints
        • Alternate Protocol 3: Flexible Ligand Docking with Similarity
        • Support Protocol 1: Ligand Preparation
        • Support Protocol 2: Receptor Preparation
        • Support Protocol 3: Software Installation
        • Guidelines for Understanding Results
        • Commentary
        • Literature Cited
        • Figures
             
         
        GO TO THE FULL PROTOCOL:
        PDF or HTML at Wiley Online Library

        Materials

         
        GO TO THE FULL PROTOCOL:
        PDF or HTML at Wiley Online Library

        Figures

        •   Figure 8.12.1 Figure of dependencies among protocols.
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        •   Figure 8.12.2 The Receptor tab of the Receptor Grid Generation panel.
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        •   Figure 8.12.3 The Site tab of the Receptor Grid Generation panel.
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        •   Figure 8.12.4 The Site – Advanced Settings dialog box.
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        •   Figure 8.12.5 The Settings tab of the Glide ligand‐docking panel.
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        •   Figure 8.12.6 The Ligands tab of the Glide ligand panel.
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        •   Figure 8.12.7 The Ligand Docking ‐ Start menu.
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        •   Figure 8.12.8 The Maestro Monitor panel monitoring a Glide docking job.
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        •   Figure 8.12.9 The Constraints tab of the Receptor Grid Generation panel showing the Positional subtab.
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        •   Figure 8.12.10 The New Position dialog box.
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        •   Figure 8.12.11 The Constraints tab of the Receptor Grid Generation panel showing the H‐bond/Metal subtab.
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        •   Figure 8.12.12 The Constraints tab of the Receptor Grid Generation panel showing the Hydrophobic subtab.
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        •   Figure 8.12.13 Hydrophobic constraint regions displayed in the Maestro Workspace.
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        •   Figure 8.12.14 The Constraints tab of the Glide Ligand Docking panel.
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        •   Figure 8.12.15 The Similarity tab of the Glide Ligand Docking panel.
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        •   Figure 8.12.16 The LigPrep Panel.
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        •   Figure 8.12.17 The Protein Preparation Wizard panel.
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        •   Figure 8.12.18 The Selected tautomeric/protonation state of a ligand displayed in the Workspace.
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        •   Figure 8.12.19 Examples of well‐docked and poorly‐docked ligands from docking co‐crystallized ligands back into their prepared proteins. Ligands in blue are the native structures and those in green are the top‐ranked docked structures. RMSDs for docked 3tpi, 1apt, 1tmn, and 1dhf ligands are 0.44, 1.26, 1.97, and 5.44 Å, respectively.
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        •   Figure 8.12.20 Three hypothetical enrichment curves. In the high early enrichment example 90% of known active ligands are found before 10% of the known decoy ligands were recovered. In the moderate early enrichment example 30% of known active ligands were found before 10% of the known decoy ligands were recovered. These results stand in contrast to what would be expected by chance, shown in the even distribution curve.
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        Videos

        Literature Cited

           Friesner, R.A., Banks, J.L., Murphy, R.B., Halgren, T.A., Klicic, J.J., Mainz, D.T., Repasky, M.P., Knoll, E.H., Shelley, M., Perry, J.K., Shaw, D.E., Francis, P., and Shenkin, P.S. 2004. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem. 47:1739‐1749.
           Friesner, R.A., Murphy, R.B., Repasky, M.P., Frye, L.L., Greenwood, J.R., Halgren, T.A., Sanschagrin, P.C., and Mainz, D.T. 2006. Extra precision Glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein‐ligand complexes. J. Med. Chem. 49:6177‐6196.
           Halgren, T.A., Murphy, R.B., Friesner, R.A., Beard, H.S., Frye, L.L., Pollard, W.T., and Banks, J.L. 2004. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem. 47:1750‐1759.
           Kontoyianni, M., McClellan, L.M., and Sokol, G.S. 2004. Evaluation of docking performance: Comparative data on docking algorithms. J. Med. Chem. 47:558‐565.
           Krovat, E.M., Steindl, T., and Langer, T. 2005. Recent advances in docking and scoring. Curr. Comp. Aid Drug Des. 1:93‐102.
           Pearlman, D.A. and Charifson, P.S. 2001. Improved scoring of ligand‐protein interactions using OWFEG free energy grids. J. Med. Chem. 44:502‐511.
           Perola, E., Walters, W.P., and Charifson, P.S. 2004. A detailed comparison of current docking and scoring methods on systems of pharmaceutical relevance. Proteins 56:235‐249.
           Sherman, W., Day, T., Jacobson, M.P., Friesner, R.A., and Farid, R. 2006. Novel procedure for modeling ligand/receptor induced fit effects. J. Med. Chem. 49:534‐553.
           Teague, S.J. 1996. Implications of protein flexibility for drug discovery. Nature Rev. Drug Discovery 9:175‐186.
        Internet Resources
           http://www.schrodinger.com
        GO TO THE FULL PROTOCOL:
        PDF or HTML at Wiley Online Library
         
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