Introduction to Molecular Docking

Molecular Docking

Computational docking is widely used for study of protein-ligand interactions and for drug discovery and development.

Tests the fit of a molecule in a protein binding site.

Sampling of large number of possible configurations.
Score for fit using one of several different scoring functions.

Docking – types

Bound-Bound Docking
- Docking where both the docked molecules are from a bound conformation.
Bound-Unbound Docking
- Docking where one of the molecules is from a bound confomation.
Unbound-Unbound Docking
- Docking where both the docked molecules are from an unbound conformation.

Input – target receptor

Missing loops and sidechains, mutations.

Low occupancy, high displacement parameters.

Water molecules – enclosed in the targeted binding pocket, interacting with the co-crystalized ligand.

Cofactors - should be considered if they are involved in ligand recognition e.g. heme.

Hydrogen atoms – added as a part of receptor preparation in all docking programs.

In case no experimentally determined structure is available then homology derived structural model can be used.

Bender et al, Nat Protoc 16, 4799–4832 (2021)

Input – Binding site

A high-resolution ligand-bound structure.

holo conformation performs better than apo.

geometries of the binding pocket are better defined.

In the absence of defined binding pocket, prediction methods can be used to find potential binding sites.

Generally small buried binding sites better than large exposed ones.

Bender et al, Nat Protoc 16, 4799–4832 (2021)

Docking – control

Using a known inhibitor(s) to optimize binding pocket and docking parameters.

Docking should be able to reproduce the binding mode of the known inhibitor.

Known actives should rank higher against a background of decoy molecules.

Negative control – known inactives; should rank low in docking.

Without known ligands as positive controls, one is at a substantial disadvantage at setting up docking calculations.

Bender et al, Nat Protoc 16, 4799–4832 (2021)

Docking – Hit selection

Compounds may be filtered for both positive and negative features.

Docked orientation has favorable interactions with key residues.

binding affinity, ligand efficiency, solubility, toxicity, etc.

Closely related compounds will likely dock in similar poses with similar score, cluster compounds by 2D structure similarity after all other filters have been used and only select the best scoring cluster representative for testing.

Bender et al, Nat Protoc 16, 4799–4832 (2021)