Computational protein–ligand docking and virtual drug screening with the AutoDock suite

Authors

Stefano Forli, Ruth Huey, Michael E Pique, Michel F Sanner, David S Goodsell & Arthur J Olson

Summary

Computational docking can be used to predict bound conformations and free energies of binding for small-molecule ligands to macromolecular targets. Docking is widely used for the study of biomolecular interactions and mechanisms, and it is applied to structure-based drug design. The methods are fast enough to allow virtual screening of ligand libraries containing tens of thousands of compounds. This protocol covers the docking and virtual screening methods provided by the AutoDock suite of programs, including a basic docking of a drug molecule with an anticancer target, a virtual screen of this target with a small ligand library, docking with selective receptor flexibility, active site prediction and docking with explicit hydration. The entire protocol will require ~5 h.

Materials

1. Software

• OpenBabel
• Chimera
• ADT
• AUTODOCK  

2. System

• Linux;
• or Macintosh;
• or Windows PC(32 bit);
• Internet access

Procedure

Single docking with Autodock4.2.6 on window PC(32-bit)

A. Coordinate file for ligand 

 1. Download ligand from ZINC library or PubChem database in PDBQT or mol2,
cif and sdf formmat.

2. Transform the non-PDBQT file for ligand to PDBQT format by OpenBabel.

1.  Open imatinib.sdf file in OpenBabel.
2. Choose 3D coordinate, and click transform.
3. Choose the imatinib.PDBQT format to save at C:\Autodock.

3. Remove the ligands in the receptor by Chimera software.

1. Download the 3D coordinate of the receptor 1iep_receptorH.pdb from PDB database.
2. Open the 3D coordinate of the 1iep_receptorH.pdb in Chimera software.
3. Choose Select->Structure->ligand.
4. Choose Atom->Atom/bonds->delete.
5. Choose File->save pdb->save as 1iep_receptor_noligand.pdb at C:\Autodock.

4.  Prepare the ligands and receptors for docking by Autodock4.2.6

1. Ligand->Input->Open->ligand.pdbqt
2. Grid->Macromolecule->open->receptor.pdbqt
3. Note: Here we explain how to re-position a ligand independently of other molecules using ADT/PMV. Note that AutoDock moves ligands inside a grid when initial position of a ligand is outside of bounding box.

   Step 1) Click on DejaVu GUI icon (3Dgeom.gif) on the Toolbar.

   Step 2) Select molecule of interest in "DejaVu GUI" window under Object tree. In this example, the molecule we are moving is called "HIS".

   dejavu.png

   Step 3) Click on Preferences menu in "DejaVu GUI" window and uncheck "Transf. Root Only" radio button. This now allows molecules to be moved independently of one-another.

   Step 4) Re-position molecule in 3D Viewer. See "Basic key and mouse bindings"

   Step 5) Select the molecule you have re-positioned in the dashboard of PMV. This is required since PMV can save only one molecule at a time. If you have none selected, it assumes that all are selected.

   Positioning the ligand, in PMV.

   Step 6) Save transformed coordinates using "File → Save → Write PDB". Make sure to click on "Save Tranformed Coords" radio-button in "Write Options" window, otherwise ADT saves the original, un-transformed coordinates.

   write.png

4. Grid->SetMapTypes->ChooseLigand
5. Grid->GridBox->Center->CenterOnLigand
6. File->CloseSavingCurrent->
7. Grid->Output->SaveGPF
8. Win+R to run cmd and input command: "cd/d C:\Autodock"
9. Win+R to run cmd and input command: "C:\Programm\The Scripps Research Institute\Autodock\4.2.6\autogrid.exe" -p imatinib_Abl.gpf -l imatinib_Abl.glg

5. Docking with ADT by Autodock4.2.6

1. Docking->Macromolecule->SetRigidFilename(choose receptor)
2. Docking->ligand->Choose(choose ligand)
3. Docking->SearchParameters->GeneticAlgorithmParameters (by default except Setting Number of GA runs to 50)
4. Docking->Output->LamarkkianGA->imatinib_Abl.dpf
5. Win+R to run cmd and input commmand: "C:\Programm\The Scripps Research Institute\Autodock\4.2.6\autodock.exe" -p imatinib_Abl.dpf -l imatinib_Abl.dlg

6. To visualize the docking results with Autodock4.2.6

1. Analyze -> Dockings -> OpenAutoDockVinaResult ->imatinib_Abl.dlg
2. Analyze -> Macromolecule -> Open
3. Analyze ->Dockings -> ShowInteractions
4. Analyze ->Docking ->Load to open a clickable window with ranked conformations and energies.

Further details

Sargis Dallakyan contributes to the Positioning ligands with ADT.

References

1. Stefano Forli, Ruth Huey, Michael E Pique, Michel F Sanner, David S Goodsell & Arthur J Olson. Computational protein–ligand docking and virtual drug screening with the AutoDock suite. nature protocols.2016. 11(5) :905-920.

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