Selective and Effective: Current Progress in Computational Structure-Based Drug Discovery of Targeted Covalent Inhibitors

Covalent (irreversible) enzyme inhibitors are an important group of actual or potential therapeutics. For example, Aspirin is an irreversible inhibitor of the cyclooxygenase enzyme. Evaluating covalent inhibitors in the drug discovery is exceptionally challenging, because their overall inhibitory potency consists of two separate but intertwined contributions: (1) initial binding affinity and (2) chemical reactivity. It is especially difficult to reliably asses the kinetic mechanism of inhibition. This paper describes an objective statistical approach that can be used to decide between two alternate kinetic mechanisms of covalent enzyme inhibition, from kinetic experiments based on the standard "kobs" method [Copeland (2013) "Evaluation of Enzyme Inhibitors in Drug Discovery", section 9.1]. The two alternatives are either a two-step kinetic mechanism, which involves a reversibly formed noncovalent intermediate, or a one-step kinetic mechanism, proceeding in a single bimolecular step. The proposed statistical toolkit uses four independent methods to arrive at a reliable mechanistic conclusion. The results are illustrated by using recently published experimental data on the inhibition of two different protein kinases by the experimental drugs ibrutinib (PCI-32765) and acalabrutinib [Hopper et al. (2020) J. Pharm. Exp. Therap. 372, 331–338].

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Profiling the Proteome-Wide Selectivity of Diverse Electrophiles

10.26434/chemrxiv.14186561.v1 ◽

2021 ◽

Author(s):

Patrick R. A. Zanon ◽

Fengchao Yu ◽

Patricia Musacchio ◽

Lisa Lewald ◽

Michael Zollo ◽

...

Keyword(s):

Amino Acids ◽

Drug Discovery ◽

Cysteine Residues ◽

Covalent Inhibitors ◽

Reactive Groups

<a>Targeted covalent inhibitors are powerful entities in drug discovery, but their application has so far mainly been limited to addressing cysteine residues. The development of cysteine-directed covalent inhibitors has largely profited from determining their proteome-wide selectivity using competitive residue-specific proteomics. Several probes have recently been described to monitor other amino acids using this technology and many more electrophiles exist to modify proteins. Nevertheless, a direct, proteome‑wide comparison of the selectivity of diverse probes is still entirely missing. Here, we developed a completely unbiased workflow to analyse electrophile selectivity proteome‑wide and applied it to directly compare 54 alkyne probes containing diverse reactive groups. In this way, we verified and newly identified probes to monitor a total of nine different amino acids as well as the N‑terminus proteome‑wide. This selection includes the first probes to globally monitor tryptophans, histidines and arginines as well as novel tailored probes for methionines, aspartates and glutamates.</a>

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Covalent Docking in Drug Discovery: Scope and Limitations

Current Pharmaceutical Design ◽

10.2174/1381612824999201105164942 ◽

2020 ◽

Vol 26 (44) ◽

pp. 5684-5699

Author(s):

Andrea Scarpino ◽

György G. Ferenczy ◽

György M. Keserű

Keyword(s):

Drug Discovery ◽

Covalent Bond ◽

Binding Mode ◽

Chemical Probes ◽

Comprehensive Overview ◽

Computational Tools ◽

Covalent Inhibitors ◽

Covalent Docking ◽

Docking And Scoring ◽

Covalent Ligands

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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Faculty Opinions recommendation of Drug discovery considerations in the development of covalent inhibitors.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718205712.793488388 ◽

2013 ◽

Author(s):

John Lowe

Keyword(s):

Drug Discovery ◽

Covalent Inhibitors

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Covalent inhibitors: a rational approach to drug discovery

RSC Medicinal Chemistry ◽

10.1039/d0md00154f ◽

2020 ◽

Vol 11 (8) ◽

pp. 876-884 ◽

Cited By ~ 4

Author(s):

Fandi Sutanto ◽

Markella Konstantinidou ◽

Alexander Dömling

Keyword(s):

Drug Discovery ◽

Rational Approach ◽

Future Perspectives ◽

Recent Advances ◽

Covalent Inhibitors

In this review we provide a brief historic overview of covalent inhibitors and summarize recent advances focusing on developments in the last decade. Applications in challenging targets and future perspectives are also discussed.

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