Cov_DOX: A Method for Structure Prediction of Covalent Protein–Ligand Bindings

A handful
of molecular docking tools have been extended to enable
a covalent docking. However, all of them face the challenge brought
by the covalent bond between proteins and ligands. Many covalent drug
design scenarios still heavily rely on demanding crystallographic
experiments for accurate binding structures. Aiming at filling the
gap between covalent dockings and crystallographic experiments, we
develop and validate a hybrid method, dubbed as Cov_DOX, in this work.
Cov_DOX achieves an overall success rate of 81% with RMSD < 2 Å
for the Top 1 pose prediction in the validation against a test set
including 405 crystal structures for covalent protein–ligand
complexes, covering various types of the warhead chemistry and receptors.
Such accuracy is not far from the much more demanding crystallographic
experiments, in sharp contrast to the performance of the covalent
docking front runners (success rate: 40–60%).