Agenda & Welcome (2 hr session) An Introduction to Docking in Maestro Introduction to the Study Protein preparation Glide grid generation

and SP docking XP docking Post-docking analysis

- Interaction fingerprints

Introduction
The drugs Zovirax and Vectavir are two well-known and highly prescribed anti-viral drugs that target thymidine kinase (TK) in Herpes Simples Virus (HSV). There are also many Novel inhibitors for this system found in literature and we will be looking at one example of a Novel inhibitor along with the 2 well-known drugs. We will study the binding of these compounds using docking, and post-docking filtering to understand which ligand is more effective in its role in TK and why. More information on the compounds can be found here: http://en.wikipedia.org/wiki/Aciclovir

Pre-generated Work in Maestro

Protein Preparation 1. Open and new Project and save it 2. Import 3 pdb files into your Project Table
Ac, P, N crystal structures in TK system These are your raw materials to start with

3. Duplicate Ac entry to a new group and prepare it with the Protein Prep Wizard
The pre-generated files for preparation of P and N complexes can be imported into Maestro After import, see how these files are of a similar layout

4. Examine the final min structures for each Ac, P and N to see the different protein-ligand interactions.

Glide Protein Grids & SP Docking 1. Now you are ready to perform docking, so import file material for docking.mae
Or try to create your own Group called Material for Docking from the files in your Project (see next slide) If you need it, a pre-generated one exists... glide-grid_aciclovir.zip

2. Create the protein grid file for Ac

3. Dock 3 ligands Ac, P and N with Glide-SP, and note the Gscores on completion, and examine complexes in the workspace for their different protein-ligand interactions

Group Material for Docking

1 protein, 3 ligands

Glide XP Docking 1. Load the pre-generated XP glide results into Glide XP viewer
GlideXP_3ligands.Xpdes

2. Examine the contributions of the Gscore in this table.

Note, some can be visualised in the workspace. Note, the high contribution to Hbond pair and electrostatic rewards terms

3. Why does P have the highest Gscore?

4. From SP docking, this detailed observation was not entirely obvious

SIFts - A post docking method for highliting key protein-ligand interactions 1. Lets use a different metric than Gscore to look at docking results
SIFts look at interaction patterns in the active site for docked ligands, and display them clearly in a plot

2. Import GlideXP_3ligands_pv.maegz and run SIFts to observe the results

Choose to see Hbond-donors only from the SIFT panel (interaction to display)
GLN 125 w/ and ARG - 176 are interactions picked up by both Ac and P, but not N.

Study the other interaction types from the SIFT panel

Do you see anything that distinguishes the 3 ligands?

SIFT Plot, for highliting key protein-ligand interactions

Novel Inhibitor (lig3)

Aciclovir (lig2)

Penciclovir

GLN 125

ARG 176

TRP 88 Aromatic/Hydrophobic and sidechain

Observing hydrophobic interactions

1. Use the hydrophobic-interactions-display script to verify what youve found from the SIFTs analysis
Scripts > Workspace > Display hydrophobic interactions...

Observing hydrophobic interactions

TRP 88 Aromatic/Hydrophobic and sidechain

Conclusions
From SP Docking
docked ligands are ranked P, A, N in TK system Hbond counts are 5, 5, 1 respectively If you did a similar mmgbsa study you would see the same trend as Gscore

From XP docking, we can explain why P has the best interaction with the protein
High Hbond pair correlation and electrostatic rewards

Using SiFTs, we see that there is a difference in the key interactions between the 3 ligands
Using Sidechain interactions and Hydrophobic/Aromatic Residues, TRP 88 plays a role in P-binding Visualising these hydrophobic interactions in Maestro shows that P does have much greater level of interaction than the other ligands, and this could explain its better interaction energy.

Saving and Sharing Project Files

Saving projects
A Project is a directory of structures and data. Once you save your project, further changes you make to the Project Table are automatically saved for you while you work. This means you can return to this project later. Go to the File menu and choose Save Project As In the File name box, type a name for your project, such as tutorial. Click the Save button.

If you quit Maestro and want to re-open this project later, go to the File menu and choose Open Project This will open a file chooser so you can select a project.

Sharing projects

To share your project: Go to the File menu and choose Export Project Provide a filename to create a.zip file of your project that you can share.

To open a project that someone shared with you: Just double-click on the project file icon on your Desktop OR Go to the File menu and choose Open Project Navigate to the location of the .zip file of the shared project Double-click it to open.