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22.8 Virtual Ligand Screening Tutorials
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[ VLS - Ricin | VLS - Cyclooxygenase | Docking a Markush Generated Library ]

22.8.1 Virtual Ligand Screening to Ricin Receptor


Objective

To perform virtual screening into the ricin receptor.

Instructions

22.8.2 Virtual Ligand Screening to Cyclooxygenase


Objective: To dock indomethacin and perform virtual screening of a database of COX inhibitors into the Cyclooxygenase receptor.

Retrieve the Cyclooxygenase receptor 4cox from the protein databank.

NOTE: To delete molecules you need to select them in the ICM Workspace and then right click and select delete. A range of molecules can be selected by clicking on one and whilst holding the Shift button click on the last molecule. Non-contiguous selections can be made using the Ctrl button.

Converting the Ligand and Receptor into an ICM Object.

Setting up the docking experiment

To compare the docked pose with the crystal structure - we need to rename the first object 4cox to 4cox_receptor (or just delete the first object) and then double click on 4cox in the PDBSearchResults table we used earlier.

Now we will dock Vioxx into the Cox receptor

Now let us perform a virtual screen of a database of COX inhibitors

You can check up on the progress of the docking by selecting Windows/Background Jobs. A messsage will be displayed on the screen when the docking is finished.

22.8.3 Docking a Markush Library


REQ_352

Background Once a lead compound has been identified by virtual screening, experimentally tested for activity and crystallized to confirm the docked pose then you may want to try and optimize the compound by modifying the scaffold and improve the ligand-receptor interactions. One way to do this is to enumerate a Markush library and dock that but a more direct and quicker method is to generate a focused Markush library and then dock on the fly. In this example we will use the roscovitine ligand bound to CDK5 as a scaffold to generate a focused Markush library and then identify compounds which may have better receptor interactions than roscovitine.

Step 1: Load the PDB File and Convert to ICM Object

Step 2: Inspect the ligand binding pose and identify positions to add new substituents.

Step 3: Extract the ligand and draw Markush structure

Step 4: Create Markush Combinatorial Library

Step 5: Dock Markush Combinatorial Library

Step 6: Make a focused Markush library

Step 7: Dock focused Markush library

Step 7: Evaluate results

The 2nd compound on the list is the original ligand in the 1UNL structure of CDK5 whilst the generation and screening of a Markush based library has led to the identification of a better binder in terms of ICM score. The compound ranked one has a bromine attached to a ring in the R1 position.



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Re-Dock an Inhibitor to Ricin Crystal Structure
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