Journal ArticleDOI
Targeted Covalent Inhibitors for Drug Design.
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TLDR
The covalent inhibitor approach is rapidly gaining acceptance as a valuable tool in drug discovery, and is poised to make a major impact on the design of enzyme inhibitors and receptor modulators.Abstract:
In contrast to the traditional mechanism of drug action that relies on the reversible, noncovalent interaction of a ligand with its biological target, a targeted covalent inhibitor (TCI) is designed such that the initial, reversible association is followed by the formation of a covalent bond between an electrophile on the ligand and a nucleophilic center in the protein. Although this approach offers a variety of potential benefits (high potency and extended duration of action), concerns over the possible toxicological consequences of protein haptenization have hindered the development of the TCI concept. Recently, approaches to mitigate the risk of serious adverse reactions to this new class of agent have emerged, thus stimulating interest in the field and leading to authorization of the first cadre of TCIs to be marketed. The covalent inhibitor approach is rapidly gaining acceptance as a valuable tool in drug discovery, and is poised to make a major impact on the design of enzyme inhibitors and receptor modulators.read more
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Journal ArticleDOI
Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology
Matthias Gehringer,Stefan Laufer +1 more
TL;DR: An overview of warheads-beyond α,β-unsaturated amides-recently used in the design of targeted covalent ligands is provided, with special emphasis on the discussion of reactivity and of case studies illustrating applications in medicinal chemistry and chemical biology.
Journal ArticleDOI
Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease.
Alice Douangamath,D. Fearon,P. Gehrtz,T. Krojer,Petra Lukacik,C. David Owen,Efrat Resnick,Claire Strain-Damerell,A. Aimon,Péter Ábrányi-Balogh,José Brandão-Neto,Anna Carbery,Gemma Davison,Alexandre Dias,Thomas D. Downes,Louise Dunnett,Michael Fairhead,James D. Firth,S. Paul Jones,Aaron Keeley,G.M. Keseru,Hanna F. Klein,Mathew P. Martin,Martin E.M. Noble,Peter O'Brien,A.J. Powell,Rambabu N. Reddi,R. Skyner,M. Snee,Michael J. Waring,Conor Wild,Nir London,Frank von Delft,Martin A. Walsh +33 more
TL;DR: A large-scale screen of electrophile and non-covalent fragments is performed through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication.
Journal ArticleDOI
Rapid covalent-probe discovery by electrophile fragment screening
Efrat Resnick,Anthony R. Bradley,Jinrui Gan,Alice Douangamath,T. Krojer,R. Sethi,Paul P. Geurink,Anthony Aimon,Gabriel Amitai,Dom Bellini,James Bennett,Michael Fairhead,Oleg Fedorov,Ronen Gabizon,Jin Gan,Jingxu Guo,Alexander N. Plotnikov,Nava Reznik,Gian Filippo Ruda,Laura Diaz Saez,Verena M. Straub,T. Szommer,S. Velupillai,Daniel Zaidman,Y. Zhang,Alun R. Coker,Christopher G. Dowson,Haim Barr,Chu Wang,Kilian Huber,Paul Brennan,Paul Brennan,Huib Ovaa,Frank von Delft,Nir London +34 more
TL;DR: This study highlights the potential of electrophile-fragment screening as a practical and efficient tool for covalent-ligand discovery and hypothesized that mild electrophiles might overcome the selectivity challenge.
Journal ArticleDOI
Covalent inhibitors design and discovery
TL;DR: The goal of this article is to provide an overview of the field and to outline good practices that are needed for the proper assessment and development of covalent inhibitors as well as a good understanding of the potential and limitations of current computational methods for the design of cavalent drugs.
Journal ArticleDOI
The Cysteinome of Protein Kinases as a Target in Drug Development.
TL;DR: Recent developments of this rapidly growing area in kinase drug development are reviewed and the unique opportunities and challenges of this strategy are highlighted.
References
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Journal ArticleDOI
The resurgence of covalent drugs
TL;DR: The prevalence and pharmacological advantages of covalent drugs are surveyed, how potential risks and challenges may be addressed through innovative design, and the broad opportunities provided by targeted covalENT inhibitors are presented.