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Week 11 - Ligand Binding, Docking and Drug Discovery

How to find a ligand or drug

There are many databases which contain coordinate files for ligands, market drugs, and drug-like molecules that potentially target enzymes or receptors involved in disease.

It is possible to search similar molecules for a drug or ligand of interest via these databases.

Ligand Expo

Ligand Expo provides chemical and structural information about small molecules within the structure entries of the Protein Data Bank.

Example 1: Find the ligand for c-Abl kinase (PDB ID: 1IEP) using PDB and Ligand Expo

  1. Go to the PDB website and search 1IEP.
  2. See that one of its ligands is imatinib, an anti-cancer drug.
  3. As you notice, it has a 3-letter code: STI.
  4. Go to Ligand Expo:
  5. http://ligand-expo.rcsb.org
  6. From the menu bar, click the Search icon.

Ligand Expo search

  1. Search for the ligand using its 3-letter code (STI) by typing it into the search box and clicking Go.

Search by 3-letter code

  1. In this way you can learn molecular weight, charge, molecular shape, and formula of the ligand.
  2. You can also download the SDF (structure data file) or PDB file of this molecule to further analyze it.
  3. Click Downloads from the sub-menu bar.

Downloads

  1. Choose either SDF or PDB format to download the structure of this ligand.
  2. You can analyze this structure in Jmol, UCSF Chimera, or SPDBV.

How to find a target protein for a chosen drug or ligand

Ligand Expo has another search tool which makes finding proteins that a ligand/drug targets possible.

Example 2: Find the PDB structures that STI (imatinib) binds

  1. Go to http://ligand-expo.rcsb.org
  2. Go to Search option from the menu bar.
  3. At the very bottom of the page, there is another search option:
  4. SEARCH FOR INSTANCES OF CHEMICAL COMPONENTS BY 3-LETTER ID CODE

Search instances by 3-letter ID

  1. Click Go.
  2. You will see the list of PDB structures that contain imatinib.

How to find alternative drugs for a target protein

BindingDB

BindingDB is a public, web-accessible database of measured binding affinities, focusing chiefly on interactions of drug-target proteins with small, drug-like molecules.

Example 3: Find alternative drugs that may bind to Abl kinase (besides imatinib)

  1. Go to http://www.bindingdb.org
  2. Choose ABL from the Quick Search → Choose target option and click Go.

BindingDB search

  1. This page displays binding characteristics/parameters like ΔG°, Ki, Kd, etc.
  2. Select PD153035 (Novartis Pharmaceuticals®).
  3. You will see links beside the drug name (B.MOAD, DrugBank, Google Scholar, PDB, etc.).
  4. To learn more, go to DrugBank via the link provided.
  5. After clicking the link, a list of DrugBank IDs will be displayed. Click the uppermost ID: DB02567.
  6. You can find:
  7. chemical formula
  8. 3-letter code
  9. molecular weight
  10. water solubility
  11. SDF and PDB files of the ligand

At the same time, you can find information about the target protein (sequence, molecular weight, function, cellular processes, etc.).

ZINC Database

Example 4: Find similar drugs of zoledronic acid (ZOL) using ZINC

Another anti-cancer drug is zoledronic acid (ZOL), which targets farnesyl pyrophosphate synthetase.

  1. Find the structure of ZOL from Ligand Expo.
  2. Go to http://zinc.docking.org/
  3. Click Search and Browse from the link list on the left.
  4. You will see a box to draw a molecule.
  5. Draw zoledronic acid using the atoms and bonds around the drawing box.

ZINC drawing

  1. To draw a bond or atom, click on it first, then click on the drawing box.
  2. Set similarity to 80% from the similarity option on the left.
  3. Run Query.
  4. A list of 80% similar drugs to ZOL is displayed.

You can, for example, use one of these drugs in cell culture or animal studies and move onto phase I, II, III studies. If it works, you may design a more efficient drug to treat cancer.

Docking

Docking predicts the orientation of a ligand and its binding site on the target molecule by calculating binding affinities for each binding state.

There are several docking software options:

  • Some treat the ligand as movable and the target as stable
  • Some treat the ligand as stable and the target as movable
  • Very few consider both ligand and target as movable

AutoDock Vina

AutoDock Vina is an open-source program for drug discovery, molecular docking and virtual screening. It offers multi-core capability, high performance, and enhanced accuracy and ease of use.

AutoDock Vina has been designed and implemented by Dr. Oleg Trott in the Molecular Graphics Lab at The Scripps Research Institute.

Example 5: Predict the binding site and orientation of STI (imatinib) on Abl kinase (1IEP) using AutoDock Vina

For docking:

  • First step is to create PDBQT files, which contain positions of atoms and their charges.
  • Then, a region of the protein is specified as the site where the ligand may bind.
  • Then the program is run to calculate binding affinities of possible ligand conformations.

Notes:

  • The first model is always the one with the best binding affinity, so it is the most possible binding mode.
  • Binding modes can be visualized with AutoDock Tools.

Please watch the tutorial for AutoDock Vina:

Links to learn more and download AutoDock Vina and AutoDock Tools:

AutoDock Vina Steps

  1. Open AutoDock.
  2. Open protein PDB.
  3. Click Edit → Hydrogens → Add → select polar only.
  4. Click Grid → Macromolecule → Choose → select the protein you want to dock on.
  5. Save protein with hydrogens in PDBQT format.
  6. Select the binding pocket using Grid → Gridbox.
  7. Save coordinates of the box.
  8. Open ligand PDB (Ligand → Input → Open → ligand.pdb).
  9. Pick rotatable bonds using Ligand → Torsion Tree → Choose torsion.
  10. Save ligand as PDBQT.
  11. Now close all windows and open a command prompt and go to the folder containing your PDBQT files.
  12. Use command prompt to run Vina, or prepare a configuration file and let Vina read preferences.
  13. Prepare a configuration file: create a text file conf.txt under the same folder.
  14. Go to the Vina folder containing conf.txt and PDBQT files in a terminal.
  15. Type the command:
vina --config conf.txt –log log.txt