DOCKovalent 3.7

DOCKovalent is the covalent docking version of DOCK. Originally implemented within DOCK 3.6, it was ported over to DOCK 3.7 on March 2015. The most current publication to cite DOCKovalent is:

"Covalent docking of large libraries for the discovery of chemical probes" Nir London, Rand M Miller, Shyam Krishnan, Kenji Uchida, John J Irwin, Oliv Eidam, Lucie Gibold, Peter Cimermančič, Richard Bonnet, Brian K Shoichet & Jack Taunton. Nature Chemical Biology 10, 1066–1072 (2014) doi:10.1038/nchembio.1666

Below are instructions on various aspects related to using this version of DOCKovalent. The running example for usage would be docking of cyanoacrylamides (doubly activated Michael's acceptors) to an active site cysteine in RSK2 kinase (PDB ID: 4d9t)

Custom Ligand / Library Generation

• To generate a single / few ligands:

• To generate a large library of ligands for covalent docking:

• Currently available covalent libraries (At the Shoichet lab / cluster 2)

Protein preparation

For covalent docking we need the structure (or a model) of a protein, a crystal ligand to define the binding site, and the identity of the residue for which we want to covalently dock.

-> Download 4d9t.pdb -> Extract the protein (e.g. grep ^ATOM 4d9t.pdb > rec.pdb) -> Extract the crystal ligand (e..g grep "0JG A" 4d9t.pdb > xtal-lig.pdb) -> Execute the protein preparation script while indicating the covalent attachment point, in this case CYS 436

DOCK/proteins/blastermaster/blastermaster.py -r 4d9t.pdb --covalentResNum 436 --covalentResName CYS --covalentResAtoms HG

Interpretation of the results

• Due to the ignorance of the scoring function to the covalent bond, scores tend to be higher than non covalent docking scores, even positive at times. As an example just covalently docking a methyl on to a cysteine without it clashing with anything will give a VDW score of ~+10. So positive VDW scores should not deter you from choosing what may look by eye like a good pose.

• Different electrophiles have different inherent reactivity. This is not taken into account in any way during the docking. The docked library should be matched to the application you are interested in. If you are looking for a non-toxic compound that may be active in cells you might consider unsubstituted acrylamides that are considered mild. If on the other hand you are looking for something that can label your protein in-vitro for crystallization studies Bromo-acetamide is very very reactive. Most of the covalent docking libraries were designed with fairly mild electrophiles but keep this consideration in mind when selecting which library to dock and which compounds to test.