Discovery Studio LibDock Tutorial

Discovery Studio LibDock Tutorial Molecular docking is to place the ligand molecule at the active site of the receptor, and then evaluate the interaction between the ligand and the receptor in real time according to the principles of geometric complementarity, energy complementation, and chemical environment complementation, and find the relationship between the two molecules and the best combination mode. Molecular docking considers the effect of ligand and receptor binding as a whole, and can better avoid the situation that other methods tend to have better local effects and poor overall binding. In drug design, the molecular docking method is mainly used to search for small molecules that have good affinity with the receptor biological macromolecules from the small molecule database, conduct pharmacological tests, and discover new lead compounds from it.

Prepare molecular docking system and perform molecular docking calculation 1. Define the protein as the receptor molecule. 

In the Files Explorer, find and double-click to open the 1kim.pdb file.

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The protein will appear in a new molecular window (Figure 1).

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Click to select 1kim in the system view

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In the Tools Explorer, expand Receptor-Ligand Interactions | Define and Edit Binding Site and click "Define Receptor".

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Add the SBD_Receptor column in the system view. Define the protein molecule 1kim previously selected as the acceptor molecule for use in the next step.

Figure 1 Schematic diagram of the three-position structure of protein 2. Look for possible binding regions in the receptor 

If the crystal structure does not include H atoms, select "Chemistry | Hydrogens | Add" in the menu bar to add hydrogen.

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In the Tools Explorer, expand "Receptor-Ligand Interactions | Define and Edit Binding Site", and click "From Receptor Cavities" under the "Define Site" column.

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Find the possible binding sites in the receptor by looking for the cavity in the receptor.

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9 binding sites (Site1-9) are automatically added in the system view, that is, 9 possible binding sites are found, and the largest possible binding site is displayed in the graph view. (figure 2)

Figure 2 Finding the binding site from the receptor 3. Modify the sphere radius of the active part Click to select SBD_Site_Sphere, right-click and select "Attributes of SBD_Site_Sphere..." to open the "Sphere Object Attributes" dialog box, set the Radius option from the original 11.6 to 9, and click the OK button. (Figure 3), only include the larger binding site positions.

Figure 3 Open the Sphere Object Attributes dialog box and change the radius

Open the ligand file, find the ligand file kinase_ligands.sd in the file browser, double-click, and the ligand will open in a new window. (Figure 4)

Figure 4 Browse the ligands to be docked in tabular format 4. Open the process and modify the parameters 

Expand the "Dock Ligands |High-Throughput Screening| Dock Ligands (LibDock)" process in the Tools browser, and open the corresponding parameters of the process in the parameter browser.

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In the parameter browser, click Input Receptor and select "1kim:1kim" from the drop-down list to set the receptor protein.

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Click the Input Ligands parameter, select "kinase_ligands: All" from the drop-down list, and specify the docking ligand.

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Click the Input Site Sphere parameter, and select the coordinates and radius of the first sphere from the dropdown list.

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Click the Docking Preferences parameter, select "User Specified" from the drop-down list, and change the specific parameters of the docking calculation as needed.

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Expand the Docking Preferences parameter, click the Max Hits to Save parameter, and enter the value "10". In this tutorial, modify the default settings to reduce the conformation obtained by docking and reduce the time taken. (Figure 5)

Figure 5 Open Libdock docking process and set parameters 5. Run the molecular docking calculation and view the results 

After setting the parameters, click Run to run the job. It takes about 4 minutes to complete this assignment.

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After the job is completed, click Window|Close All to close all window files. Since the program has already saved the function, select No when asked whether to save. Double-click the molecular docking job just completed in the job browser and click "View Results" to display the pose with the best score for the ligand.

6. Browse docking poses Make sure the system view and table browser are open, otherwise press CTRL+H and CTRL+T to open. In the table browser, change the Visibility Lock status of the protein from Yes to No. After unlocking, select and delete all Sites and Binding spheres in the system view, and then re-lock the protein, that is, change the Visibility Lock status to Yes, in order to check the docking result more clearly. Display protein molecules in line mode.

Figure 6 shows the hydrogen bond between protein and ligand 

Click the up and down buttons in the table to display different ligands in the graph window.

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Select Analyze Docking Results|Visualize Interactions|Receptor-Ligand Hydrogen Interactions in the Tools browser.

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In the view window, the hydrogen bond between the acceptor atom and the ligand docking poses will be displayed by a green line. (Figure 6) In order to better observe the interaction between the receptor molecule and the ligand docking pose, the system can be rotated to obtain the best viewing angle.

Analyze the docking results 

Using the Analyze Ligand Poses process, calculate the RMSD value of the docked conformation, the hydrogen bond formed between the receptor and the docked conformation, and the close contact (van der Waals collision).

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Open the "Analyze Ligand Poses" process and modify the parameters

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Open the Analyze Docking "Results|Visualize Interactions|Analyze Ligand Pose" process in the Tools browser, and the corresponding parameters appear in the parameter browser.

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Click the "Input Ligands" parameter box, select "Molecule: All" from the drop-down list, and select all ligand conformations in the Molecule window.

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Click the "Input Receptor" parameter box and select "Molecule:1kim" from the drop-down list. Expand the "Input Receptor" parameter, click the "Hydrogen Bond" parameter box, and select "True" from the dropdown list. Expand the "Hydrogen Bond" parameter and set the "Scope" parameter to "Residue" and "Molecule".

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The number of hydrogen bonds formed between the docked posture and the entire receptor and each amino acid residue of the receptor will be calculated.

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Click the "Contacts" parameter box and select "True" from the drop-down list. Expand the "Contacts" parameter, click the "Type" parameter, and select "All" from the drop-down list. This default option calculates the polar and non-polar contacts between each docking pose and the entire receptor and each docking pose and a single amino acid residue in the receptor. Click the "Scope" parameter box and select "Residue". (Figure 7)

Figure 7 "Analyze Ligand Poses" process parameter setting