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Flexible Ligand Docking with Glide
Publication Name:
Current Protocols in Bioinformatics
Unit Number:
Unit 8.12
DOI:
10.1002/0471250953.bi0812s18
Online Posting Date:
June, 2007
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
Table of Contents
- Unit Introduction
- 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
Figures
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Figure 8.12.1 Figure of dependencies among protocols. -
Figure 8.12.2 The Receptor tab of the Receptor Grid Generation panel. -
Figure 8.12.3 The Site tab of the Receptor Grid Generation panel. -
Figure 8.12.4 The Site – Advanced Settings dialog box. -
Figure 8.12.5 The Settings tab of the Glide ligand-docking panel. -
Figure 8.12.6 The Ligands tab of the Glide ligand panel. -
Figure 8.12.7 The Ligand Docking - Start menu. -
Figure 8.12.8 The Maestro Monitor panel monitoring a Glide docking job. -
Figure 8.12.9 The Constraints tab of the Receptor Grid Generation panel showing the Positional subtab. -
Figure 8.12.10 The New Position dialog box. -
Figure 8.12.11 The Constraints tab of the Receptor Grid Generation panel showing the H-bond/Metal subtab. -
Figure 8.12.12 The Constraints tab of the Receptor Grid Generation panel showing the Hydrophobic subtab. -
Figure 8.12.13 Hydrophobic constraint regions displayed in the Maestro Workspace. -
Figure 8.12.14 The Constraints tab of the Glide Ligand Docking panel. -
Figure 8.12.15 The Similarity tab of the Glide Ligand Docking panel. -
Figure 8.12.16 The LigPrep Panel. -
Figure 8.12.17 The Protein Preparation Wizard panel. -
Figure 8.12.18 The Selected tautomeric/protonation state of a ligand displayed in the Workspace. -
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. -
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.
Videos
Literature Cited
| 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 | |
|
Get information on or to download Glide and auxiliary applications | |
