Structure based ligand discovery

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Structure based ligand discovery is the use of a macromolecular (usually protein) structure to discover new ligands - small molecules that bind stoichiometrically to the protein. There are at least three ways to do this:

  • 1. Have an expert look at the model, and draw a molecule that complements the binding site.
  • 2. Perform #1 using an automatic program. This is called de novo design.
  • 3. Dock a database of small molecules into the binding site, and rank them from best to worst.

The problem with method #1 is that it is very labor intensive, and that any compound proposed may be difficult and/or expensive to acquire. The problem with approach #2 is that the compounds may still be difficult to acquire, although there are strategies to overcome this limitation. It can also be, relatively speaking, slow.

The third approach, docking, is the one taken by DOCK and its graphical user interface, DOCK Blaster. It is particularly pragmatic when used to screen a database of compounds that can be acquired rapidly, such as those in ZINC, because the time from hypothesis to experimental test can be very short, and the project can progress rapidly.