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22.9 Induced Fit (Flexibility) Docking Tutorials
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[ Multiple Receptor | Explicit Group ]

22.9.1 Multiple Receptor Conformation Ensemble Docking Example


Background

Here we will demonstrate multiple receptor conformation docking in ICM using Aldose Reductase as an example. Aldose Reductase has a flexible loop in the ligand binding pocket vicinity which enables a variety of inhibitors to bind therefore in order to identify these ligands via docking it is necessary to sample the conformations of this loop and dock to an ensemble of structures. Step 1 to Step 3 takes you through the standard re-docking procedure and highlights the accuracy of re-docking a ligand to the receptor conformation from which it was crystallized. Step 4 demonstrates that a single conformation of the Aldose Reductase receptor cannot account for the binding of all known aldose reductase inhibitors. Step 5 outlines the steps for sampling the conformation of the flexible loop regions and generating a series of conformations (stack). Step 6 is the multiple receptor docking stage (4D docking) and the results are viewed in a hitlist with an additional column which reports the receptor conformation that the highest scoring ligand is bound to.

Step1: Prepare the Receptor

Step2: Setup the Docking Project

Step 3: Optional: Re-Docking the X-ray Ligand


Step 4: Docking a Set of Known Inhibtors

In the next part of this exercise we will try to determine if other inhibitors to this receptor could be correctly docked using this one crystal structure or if more than one representation of the receptor is needed. We have already setup the docking project and made all the required maps (Steps 1 to 3) so now let us dock a set of inhibitors to the receptor. We will dock a database called ALDR_ligs.sdf which should be present in your ICM distribution if you cannot find this example sdf file then please E mail support@molsoft.com and we will E mail it to you.

Step 5: Generating Multiple Receptor Conformations

Here we will generate multiple receptor conformations of a flexible loop in the binding pocket of 1PWM.

Warning sampling the loop may take some time.

Step 6: Docking to Multiple Receptor Conformations

22.9.2 Explicit Group Docking


[ Receptor Setup | Rotate Hydroxyls | Setup Docking | Run Docking | Explicit Docking ]

This example demonstrates how to keep certain residues as explicit during grid docking. Hydroxyls of Ser, Thr, and Tyr can be treated explicitly during docking.

NOTE Feature only available in version 3.7-2a or higher

22.9.2.1 Receptor Setup


22.9.2.2 Rotate Hydroxyls


22.9.2.3 Setup Docking


22.9.2.4 Run Docking


22.9.2.5 Explicit Docking



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