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18.1 Small Molecule Docking
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[ Receptor Considerations | Ligand Considerations | Setting up the Docking Project | Set Project Name | Setup Receptor | Review and adjust binding site | (Re)Make Receptor Maps | Begin the Docking Simulation | Interactive Docking | Batch Docking | Viewing Your Docking Results | Scan Hits | View Stack | Make a HitList | Reload ]

This section is concerned with predictions of interactions of drugs or small biological substrates (less than about 600-700 Da) to pockets of larger, more rigid, receptors (typically, protein molecules, DNA or RNA).

For accurate ligand docking, the goal is to have an adequate three-dimensional model of the receptor pocket you are planning to dock ligands to. If this is the case then ICM docking has been shown to be very accurate in a number of independent assesments.

However, there are a number of pitfalls which need to be overcome to achieve accurate ligand docking. The pitfalls are that your model is not accurate overall, does not reflect the induced fit, or alternative conformations of the receptor binding pocket are missed.

Some facts about ICM docking:

18.1.1 Receptor Considerations


If you have only a single PDB entry for your receptor, convert the protein to an ICM object, delete water molecules and irrelevant chains. However, if you have a choice between several templates, take the following into account:

18.1.2 Ligand Considerations


Usually a good start is to try to dock the known ligand(s) to the receptor model. You may also want to dock a library of compounds in order to identify lead candidates. In this case the main pitfall is that the library is too restricted, molecules are not chemically feasible or not drug-like. For peptide docking please use the protein-protein docking protocol.

NOTE: If you are docking a ligand directly from the PDB please check the bond types and formal charges of the ligand. This is discussed in the section entitled Converting a Chemical from the PDB

18.1.3 Setting up the Docking Project


ICM ligand docking procedure performs docking of the fully flexible small-molecule ligand to a known receptor 3D structure. The goal of the flexible docking calculation is prediction of correct binding geometry for each binder. ICM stochastic global optimization algorithm attempts to find the global minimum of the energy function that includes five grid potentials describing interaction of the flexible ligand with the receptor and internal conformational energy of the ligand. During this process a stack of alternative low energy conformations is saved (one of the choices in the Docking menu ). Before setting up the docking project, an ICM object of the receptor has to be created. In most cases, x-ray structure of the receptor is initially in the PDB format. Thus, it has to be converted to the ICM format. This process involves addition of the hydrogen atoms, assignment of atom types and charges from the residue templates (icm.res) and imposition of internal coordinates tree (icm-tree) on the original pdb coordinates. To convert a pdb structure into icm object is through GUI as follows:

NOTE: It is recommended that "optimize hydrogens" option is selected. To accelerate the procedure, disable the 3D graphics window (type in the terminal window unds window ) When the procedure finishes, converted object is the 'current' object in icm. You can check the results by displaying the converted structure.**REMEMBER!! If you are redocking a ligand please remember to remove the ligand from the ligand binding pocket otherwise the ligand will be included in the docking maps and you will not be able to re-dock it correctly. To remove a ligand from an object - right click on the ligand in the ICM Workspace and select "move from object". Simply undisplaying the ligand is NOT sufficient.

Follow these instructions in order:

  1. Set Project Name
  2. Setup Receptor
  3. Setup Ligand Note:Version 3.4-7f and higher does not have this option - ligand setup is selected at interactive docking or batch setup step (See Start Docking Simulation)
  4. Review and Adjust Binding Site
  5. Make Receptor Maps
  6. Start Docking Simulation
  7. View Docking Results

18.1.4 Set Project Name


Start the docking project setup by defining the project name:

Now set up the receptor. Go to Receptor Setup

18.1.5 Setup Receptor


The next step is to set up the receptor for docking.

NOTE: Other docking project names that you have entered can be found by clicking on the arrow besides the Project name data entry box.

There are different ways to enter the binding site residues

  1. Define the binding site residues, either manually e.g. a_/123,144,152 for selection by residue numbers.
  2. Graphically using the graphical selection tools such as the lasso tool (don't forget to set selection level to residue) or the icmPocketFinder function. If the residues are selected using the lasso tool or icmPocketFinder there should be green crosses surrounding the ligand binding pocket. The green crosses represent a graphical selection and are returned to a variable called as_graph type as_graph in the Binding site residues data entry box.
  3. Or possibly the easiest way (if you have a ligand in the correct place already) is to select the ligand in the icm workspace (double click on it) and then press the "Define Site Around Selected Ligand" button. This will make a graphical selection (green crosses) of the residues surrounding the ligand.
This selection is used solely to define boundaries of the docking search and the size of the grids and doesn't have to be complete, selecting some 4 residues delimiting the binding site is sufficient. Receptor setup dialog also lets you run binding site identification routine to quickly locate putative binding sites on your receptor.

NOTE: Potential ligand binding pockets can be identified using ICMPocketFinder or by clicking on the Identify Binding Sites button in the Docking/Receptor Setup.. data entry window. These two methods for identifying pockets are identical.

After the receptor setup is complete, the program normally displays the receptor with the selected binding site residues highlighted in xstick representation surrounded by a surface representation.

NOTE: At this stage of the docking setup it is a good idea to keep an eye on the terminal window. Instructions and any error messages will be displayed in the terminal window. If you do not see the terminal window select Windows/Terminal Window.

To complete the receptor setup there are two more steps:

Adjust the position of the probe (initial ligand starting position

The position of the probe (usually represented as 4 spheres in the center of the pocket) represents the initial position where sampling will begin. The default probe position is generally OK for most purposes but if you would like to move it to a critical part of the receptor so that sampling initially concentrates in that region you can do so using the middle mouse button and holding the SHIFT button for global rotation. Once you are happy with the position of the box press the enter key or click on "GO".

NOTE The probe position can be changed again using the Docking/Review/Adjust Ligand/Box.. option.

Adjust the size and/or position of the box The purple box represents the region in which maps will be generated. The box needs to be large enough to encompass the binding pocket but not too large and including regions of the receptor which are not relevant for the ligand to bind. If the binding site is correctly defined in the earlier Receptor setup then the default box size is usually fine. If it is necesary to change the box size you can use the left mouse button with the cursor at any corner of the purple box to change it.

NOTE The size of the box can be changed again using the Docking/Review/Adjust Ligand/Box.. option.

18.1.6 Review and adjust binding site


NOTE: Generally the default box ICM generates in the receptor setup stage is adequate. It is usually a good idea to double check the box encompasses all the residues you want to dock to.

ICM makes a box around the ligand binding site based on the information entered in the receptor setup section. The position of the box encompasses the residues expected to be involved in ligand binding, however you may wish to alter the size of the purple box or the position of the ligand probe (red spot).

Follow the instructions in the command line display.

NOTE: Always check that the correct project name is displayed in the data entry window.

Now go to Make Receptor Maps.

18.1.7 (Re)Make Receptor Maps


NOTE: You need to use this option if you have changed the size of the box (Review/Adjust Ligand/Box). You also need to use this option if you did not select the Make Receptor Maps Immediately option in Docking/Receptor Setup.

The next step is to construct energy maps of the environment within the docking box.

NOTE: Always check the correct project name is displayed in the data entry window.

NOTE: Calculation of the maps may take a few minutes.

Now begin the docking procedure.

18.1.8 Begin the Docking Simulation


Once the receptor and maps have been correctly set up then the docking procedure can begin.

There are two options INTERACTIVE or BATCH docking (Please note some of the options may be limited for users without ICM-VLS)

18.1.9 Interactive Docking


Use interactive docking to dock one ligand at a time in the foreground. It is ideal to use this option for small-scale docking.

Choose either Mol Table Ligand or Loaded Ligand

Interactive Docking - Mol Table Ligand If you have a chemical table already loaded into ICM you can use this option to dock them. You can read mol/mol2 or sdf files into ICM by using File/Open. They will be displayed in a table.

Interactive Docking - Loaded Ligand

If you have a ligand as an ICM object you can use this option.

18.1.10 Batch Docking


Batch Docking is used for running docking jobs in the background. It is ideal for large-scale docking jobs.

From Loaded ICM Object Your ligand will have been converted to an ICM object and loaded into ICM (File/Open) Your object will be displayed in the ICM Workspace.

From File: ICM If your ligand (s) is saved and converted to an ICM object but is not yet loaded into ICM then you need to use this option.

From File:MOL/MOL2

If your ligand is a MOL or MOL2 file then

File Formats:

MOL Format

MOL2 Format

From Indexed Database - only available with ICM-VLS

In most cases the ligand input file will be an SDF or MOL2 file. These files need to be indexed by ICM before they can be used in VLS runs (see next section of this manual). The index is used to allow fast access to an arbitrary molecular record in a large file such as an SDF file which in some cases contains over one million compounds.

To index an sdf file:

From MolCart - only available with ICM-VLS

NOTE A separate license is required for MolCart

IMPORTANT - NOW SET YOUR BATCH JOB RUNNING USING DOCKING/SMALL SET DOCKING BATCH

NOTE: NOW SET YOUR BATCH JOB RUNNING USING DOCKING/SMALL SET DOCKING BATCH}

Docking simulation is running

Docking simulation has ended message

To check the status of your docking simulation

18.1.11 Viewing Your Docking Results


Docking results can be visualized and browsed in one of the following ways.

The results of the docking are saved in the following files

PROJECTNAME_LIGANDNAME.ob #icm-object file with best solutions for each ligand PROJECTNAME_*.cnf # icm conformational stack files with multiple docked conf.

The results of the docking job using ICM-VLS (separate license required) are saved in the folling files:

PROJECTNAME_answers*a.ob #icm-object file with best solutions for each ligand

PROJECTNAME_*.cnf # icm conformational stack files with multiple docked conf.

PROJECTNAME_*.ou # output file where various messages are stored eg.SCORE

18.1.12 Results - Scan Hits


18.1.13 Docking Results - View Stack Conformations


To view the multiple positions of a single ligand in the docking simulation ranked by energy.

The Browse Stack Conformation data entry window will be displayed.

Columns in the Stack Table

i rank in stack

ener Energy kcal/mol

gvw van der Waals grid potential

gb hydrogen bonding grid potential

ge electrostatic grid potential

gs hydrophobic grid potential

Einternal is internal conformation energy of the ligand

18.1.14 Make a HIT LIST - Only available with ICM-VLS


Columns in the HitList Table

IX is the index number from the docked database

Score is the ICM score -32 and lower are generally considered good scores - but depends on the receptor (e.g. exposed pockets or pockets with metal ions mayhave higher scores than -32).

Natom is the number of atoms in docked ligand

Nflex is the number of rotatable torsions.

Hbond is Hydrogen Bond energy

Hphob is the hydrophobic energy in exposing a surface to water

VwInt is the van der Waals interaction energy (sum of gc and gh van der waals). Current version of the score uses explicit van der Waals interaction energy calculation (no grids)

Eintl is internal conformation energy of the ligand

Dsolv is the desolvation of exposed h-bond donors and acceptors.

SolEl is the solvation electrostatics energy change upon binding.

mfScore is the potential of mean force score

RecConf - if multiple receptor conformations was used Docking/Flexible Receptor/Setup 4D grid and represents the receptor conformation number.

NOTE There are a number of post-screening analysis built into the Tools panel on the right hand side of the hitlist. These are described here.

18.1.15 Reload a Docking Project


To reload a docking project.

/Docking/Set Project - Type in the Docking Project Name (Case Sensitive)

Now you can browse scan solutions etc.... and use the maps to dock another ligand.


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