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Covalent Docking in Drug Discovery: Scope and Limitations

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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.
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Keywords: Covalent docking; binding mode prediction; drug design; reactivity; targeted covalent inhibitors; virtual screening; warhead

Document Type: Review Article

Publication date: December 1, 2020

This article was made available online on November 30, 2020 as a Fast Track article with title: "Covalent Docking in Drug Discovery: Scope and Limitations".

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  • Current Pharmaceutical Design publishes timely in-depth reviews covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area. A Guest Editor who is an acknowledged authority in a therapeutic field has solicits for each issue comprehensive and timely reviews from leading researchers in the pharmaceutical industry and academia.

    Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.
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