Tutorial
Dock Ligands from a 2D Molecule Sketch
March 31, 2016
Sample to Insight
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Dock Ligands from a 2D Molecule Sketch
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Tutorial
Dock Ligands from a 2D Molecule Sketch
This tutorial takes you through the steps of downloading the freely available program Balloon
and using it with CLC Drug Discovery Workbench. Balloon supports the conversion of a 2D
molecule sketch, via SMILES string representation, to a 3D molecule structure ready to dock in the
workbench.
Molecules can be represented by so-called SMILES strings (see example in figure 1). The SMILES
string notation contains information about cis/trans isomerism and chirality as well as integral
charges. In most programs and web-sites working with molecules, the SMILES string notation
can be found and used. In programs such as ChemDraw and MarvinSketch, where molecules are
sketched in 2D (see figure 1), the molecules can also be copied as SMILES strings.
Figure 1: The molecule Compound21 sketched in ChemDraw and represented as a SMILES string.
Molecules represented as SMILES strings can be imported to the workbench, or pasted directly
into a Molecule Project. The workbench uses the freely available program Balloon, to generate
3D coordinates from the SMILES representation. In the manual, the algorithm used to generate
the 3D coordinates is described in more detail, in the 'Import molecules' section.
Example files relating to this tutorial can be imported from the Help menu (Help | Import Example
Data). The files for this tutorial are found in CLC_Data/Example Data/Fast Track Docking.
You can work quickly through the tutorial, by only following the instructions highlighted
with blue background color.
Notice, that in the end of the tutorial you can find "Good to know..." overviews ... about
molecule data in the workbench, ... about modeling protein-ligand interactions in the
workbench I and ... about modeling protein-ligand interactions in the workbench II.
Balloon as 3D Structure Generator
The freely available structure generator Balloon (http://users.abo.fi/mivainio/balloon/) is used
in two workbench features:
• The importer Import Molecules from SMILES or 2D, used to import libraries of molecules
with 2D coordinates (Mol2 or SDF format) or given as SMILES strings (.smi files) into the
workbench as a Molecule Table containing 3D molecule structures.
• The support for pasting SMILES representations of molecules into a Molecule Project and
Dock Ligands from a 2D Molecule Sketch
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Tutorial
generating a 3D structure in the process. This is exploited in this tutorial, to get a sketched
molecule into the workbench and ready for docking.
To enable these features, three simple steps should be taken:
1. Download the program Balloon for your platform from
http://users.abo.fi/mivainio/balloon/download.php
2. Place the executable (e.g. balloon.exe for Windows) on your computer. The file
MMFF94.mff, which is downloaded together with the executable, should be kept in
the same folder as the executable.
3. Specify in the workbench (Edit | Preferences | General | Small Molecule 3D Structure
Generation) where the Balloon executable is located on your computer (figure 2).
Figure 2: The Preferences settings, with the Balloon executable location specified in the bottom.
The Preferences are found in the Edit menu in the workbench.
Fast Track Docking Example
In the tutorial Exploring Protein-ligand Binding, a Binding Site Setup was created for cyclindependent kinase 2 (PDB ID 1KE5), and the co-crystallized ligand docked, to validate the setup.
The Molecule Project with the Binding Site Setup is reused in this tutorial. You can go through
the Exploring Protein-ligand Binding tutorial first, or alternatively:
Open the Molecule Project 1KE5 setup validated from Example Data/Fast Track Docking.
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A molecule has been sketched in ChemDraw (figure 1). We would like to see how this molecule
could bind to the binding site.
As seen in figure 1, the molecule Compound21 can be represented by the SMILES string
NS(=O)(c1ccc(N/C(C)=C2C(Nc3c\2cc(Cl)cc3)=O)cc1)=O
Draw Compound21 in your favorite 2D sketching program, select the molecule, and 'Copy
as SMILES',
or
copy the SMILES string directly from this tutorial (select with mouse and Ctrl-C).
Infobox: Making a useable 2D sketch
The 2D sketch should only include plain single, double, and triple bonds, and use wedge
) to specify chirality. No delocalized bonds or other more exotic bond notations
bonds (
should be used, as the SMILES notation does not support those. Specify integral charges
on atoms where relevant, they will be included in the SMILES representation.
Infobox: SMILES representation not unique
There can be different ways to write a valid SMILES string for a molecule, so depending
on the program generating the SMILES, it can look different from the one seen above.
Paste the copied SMILES string into the Molecule Project using either Ctrl-V (Cmd-V on
Mac) or right-click in the Project Tree area and choose Paste.
This will invoke a dialog box where the name of the molecule can be specified, as well as
whether a single conformation or an ensemble of low-energy conformations should be generated
(figure 3).
Figure 3: The Generate 3D structures from SMILES string dialog box.
Info box: Why generate more than one conformation?
Angles, bond distances and ring conformations are not changed during docking, and it
can therefore be relevant to dock different conformations of a ligand, especially if it has a
non-aromatic ring system.
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In the Generate 3D structures from SMILES string dialog box:
Specify the molecule name as Compound21.
Choose to generate one conformation per molecule.
Press OK.
Now a notification will show in the bottom left of the 3D view, stating that the structure generation
has started. This means that the input is sent to Balloon. Shortly after, another notification will
state that Balloon has finished the structure generation, and a new molecule is added to the
Ligands category (example file 1KE5 pasted SMILES).
Double-click the newly added ligand in the Project Tree, to zoom and fit around it.
Inspect the molecule visually, and check if there are new issues in the Issues view related to the
pasted molecule (shift to the Issues view by clicking the ( )-icon below the 3D view). No issues
should be found, and now we are ready to dock the ligand.
Select the newly added ligand in the Project Tree.
Press the Dock Ligand button found below the Project Tree.
This will start the docking of the ligand.
After a while, the docking is done, and a new docking result added to the Molecule Project
(example file 1KE5 pasted SMILES docked). Double-click the newly added docking result in the
Project Tree, to get a view of the binding mode.
Figure 4: The docking of the co-crystallized ligand (carbon atoms in blue) and the docking of
Compound21 (carbon atoms in pink) seen together. The hydrogen bonds for the two binders are
shown as blue dashed lines (the visualization is saved on the example file '1KE5 pasted SMILES
docked' as 'Binding modes compared').
Inspect the binding using the visualization options available from the quick-style buttons below
the Project Tree, and use the options for visualizing binding site interactions available from the
context menus on the docking results (figure 4 and figure 5).
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Figure 5: From the context menu on a selected ligand or docking result, hydrogen bonds can be
shown or hidden and an atom group with interacting residues and molecules can be created.
You can now sketch a new molecule, and paste it as a SMILES string into the workbench, to see
it docking to the binding site.
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Good to know...
... about molecule data in the workbench
Molecule data can be stored in either Molecule Projects (
) or Molecule Tables (
).
Molecule Project (3D view)
Content: Molecule 3D structures listed as Project Tree entries, molecule data, Binding Site
Setup, binding pockets, custom atom groups, and connection to protein sequences.
Molecule Table
Content: Molecule 3D structures listed as table entries and molecule data.
Connect to a Molecule Project to see molecules in 3D
Molecules selected in table show up as 'guests' in the connected Molecule Project (indicated by
red square above).
Dock Ligands from a 2D Molecule Sketch
Tutorial
Good to know...
... about modeling protein-ligand interactions in the workbench I
Dock and Screen Ligands
Molecule interactions are modeled and analyzed between ligands and a Binding Site Setup.
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Dock Ligands from a 2D Molecule Sketch
Tutorial
Good to know...
... about modeling protein-ligand interactions in the workbench II
One-click Docking
Molecule interactions are modeled and analyzed between ligands and a Binding Site Setup.
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