In recent decades the pharmaceutical industry has not favoured covalent ligands. Perhaps this is why most virtual screening studies have ignored that possibility.
I have demonstrated to my satisfaction that it is possible to dock a variety of covalent molecules with standard warheads as well as a few novel ones. This includes molecules which bridge the CYS(145) HIS(41) gap etc as well as interact elsewhere in the binding site. The scoring functions should be better than “selection by eye” but do not attempt to address the reversibility of the binding nor do I have any reasons to beleive they will perform better than non-covalent scoring functions.
Some of the molecules I’ve docked are similar to previous submissions but many are either from commercially available screening libraries, virtual libraries or dream libraries (where the chemistry required eg for heterocyclic ring closure is in principle possible but not trivial).
I’m not sure what selection process would be best. Partition into subsets based on other residue interactions or by electron withdrawing/donating properties of groups connected to the warhead (which have the potential to impact the kinetics). An alternative approach would be molecular properties …
Thoughts and suggestions are welcome!