DOCK Blaster:Preliminaries

Docking requires three things: a target, a database, and a docking program. DOCK Blaster uses DOCK 3.5.54 as the docking program and ZINC as the database. You must choose a target structure for docking. You will also need to have some idea of the binding site you wish to target, as proteins often contain more than one eligible site. You may also have additional information such as actives and inactives, which can be useful for assessing docking performance.

What is the question?

The most common use of docking is to answer the question: 1) What compounds should I purchase to test for activity against my protein? Many people will also want to know: 2) Are the docking results worth spending time and money testing?

Ideally, we would like to answer question 2 first. DOCK Blaster's approach is to collect available control information, in the form of bound ligands, actives and inactives that may be reported in the literature or patents, or known from other sources. DOCK Blaster performs a preliminary docking study which attempts to recapitulate known experimental information. If it cannot do this, it does not necessairily mean that docking "does not work". There may be good mitigating circumstances. However, it should raise doubt in your mind, if docking cannot re-discover what you already know.

Here we consider some of the most typical scenarios for a docking project, and attempt to point out what you should keep in mind before you start docking. Remember, this is research! So be sure to do controls if you can, and be skeptical!

This is a good time to remind you that docking is just one of many techniques for ligand discovery. In particular, if actives against a target are already known, the simplest way may be to simply look for analogs and derivatives via ligand based methods.

What do I know?

To use docking you need to have a structure of the target. Let us consider the possible scenarios.

Only one crystal structure, good quality, with ligand bound

This is a nice situation to be in. Your target is in a ligand bound conformation, and your ligand is a valuable control with which to assess performance. Although there are many reasons why docking may still be problematic, you at least have a good chance of being able to evaluate how well the docking program performs, and whether it can be expected to predictive.

Only one crystal structure, good quality, no ligand bound

This is often a close runner up to having a ligand bound crystal structure, as in many cases there is not a lot of induced fit. It may be worth looking for crystal structures of highly similar targets, in case one has a ligand bound. That might give an indication of the amount of induced fit in the target that might be expected on ligand binding. A drawback to this scenario is the lack of a crystallographic control. It may be worthwhile trying to model in a ligand, if you know one.

No good crystal structure available

Homology model

Homology models vary widely in their usefullness for docking. This is a topic of considerable current interest. Generally, the higher the identity of the target to the scaffold the more reliable the model will be. Pay attention to amino acid substitutions in the binding site. Also, if several scaffolds are available, consider the sequence identity in the binding site as well as the overall sequence identity as a figure of merit for selecting the best model for docking.

NMR structure

NMR structures can also be useful for docking, particularly if the binding site is fairly rigid. Ligand controls can be helpful for assessing the performance of the docking.

I cannot acquire a structure of the target

You cannot start docking without a 3D atomic model of your target. Ask colleages for advice. Search the PDB or use ModBase.

More than one good crystal structure available

You are both lucky and cursed, because whereas you have more information, it may be unclear which model to choose. We can make several suggestions:

• Consider superimposing the structures to look for variability in the binding site.
• Consider both the overall resolution and the B factors of atoms in the binding site when considering which model is best.
• You may be able to use atoms from multiple bound ligands for the "hot spots".

== I have additional information

Actives and Inactives

Several sources of information:

• positive controls (actives)
• negative controls (inactives)

Special knowledge

• pH at which the structure was solved / is biologically relevant