Binding Mode Prediction and Virtual Screening Applications by Covalent Docking.

The mechanism of action of covalent drugs involves the formation of a bond between their electrophilic warhead group and a nucleophilic residue of the protein target. The recent advances in covalent drug discovery have accelerated the development of computational tools for the design and characterization of covalent binders. Covalent docking algorithms can predict the binding mode of covalent ligands by modeling the bonds and interactions formed at the reaction site. Their scoring functions can estimate the relative binding affinity of ligands towards the target of interest, thus allowing virtual screening of compound libraries. However, most of the scoring schemes have no specific terms for the bond formation, and therefore it prevents the direct comparison of warheads with different intrinsic reactivity. Herein, we describe a protocol for the binding mode prediction of covalent ligands, a typical virtual screening of compound sets with a single warhead chemistry, and an alternative approach to screen libraries that include various warhead types, as applied in recently validated studies.