Drug discovery efforts for new covalent inhibitors have drastically increased in the last few years.
The binding mechanism of covalent compounds entails the formation of a chemical bond between their electrophilic
warhead group and the protein of interest. The use of moderately reactive warheads targeting nonconserved
nucleophilic residues can improve the affinity and selectivity profiles of covalent binders as compared
to their non-covalent analogs. Recent advances have also enabled their use as chemical probes to disclose
novel and also less tractable targets. Increasing interest in covalent drug discovery prompted the development
of new computational tools, including covalent docking methods, that are available to predict the binding mode
and affinity of covalent ligands. These tools integrate conventional non-covalent docking and scoring schemes
by modeling the newly formed covalent bond and the interactions occurring at the reaction site. In this review,
we provide a thorough analysis of state-of-the-art covalent docking programs by highlighting their main features
and current limitations. Focusing on the implemented algorithms, we show the differences in handling the
formation of the new covalent bond and their relative impact on the prediction. This analysis provides a comprehensive
overview of the current technology and suggests future improvements in computer-aided covalent
drug design. Finally, discussing successful retrospective and prospective covalent docking-based virtual screening
applications, we intend to identify best practices for the drug discovery community.