Kinase inhibitors: the road ahead

Nature Reviews Drug Discovery, Journal Year: 2018, Volume and Issue: 17(5), P. 353 - 377

Published: March 16, 2018

Language: Английский

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Proteome-wide covalent ligand discovery in native biological systems

Nature, Journal Year: 2016, Volume and Issue: 534(7608), P. 570 - 574

Published: June 14, 2016

Language: Английский

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Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology

Journal of Medicinal Chemistry, Journal Year: 2018, Volume and Issue: 62(12), P. 5673 - 5724

Published: Dec. 19, 2018

Targeted covalent inhibitors (TCIs) are designed to bind poorly conserved amino acids by means of reactive groups, the so-called warheads. Currently, targeting noncatalytic cysteine residues with acrylamides and other α,β-unsaturated carbonyl compounds is predominant strategy in TCI development. The recent ascent drugs has stimulated considerable efforts characterize alternative warheads for covalent-reversible irreversible engagement as well acids. This Perspective article provides an overview warheads-beyond amides-recently used design targeted ligands. Promising groups that have not yet demonstrated their utility development also highlighted. Special emphasis placed on discussion reactivity case studies illustrating applications medicinal chemistry chemical biology.

Language: Английский

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Advances in covalent drug discovery

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(12), P. 881 - 898

Published: Aug. 25, 2022

Language: Английский

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Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies

Drug Discovery Today, Journal Year: 2015, Volume and Issue: 20(9), P. 1061 - 1073

Published: May 23, 2015

Language: Английский

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Targeted Covalent Inhibitors for Drug Design

Angewandte Chemie International Edition, Journal Year: 2016, Volume and Issue: 55(43), P. 13408 - 13421

Published: Aug. 19, 2016

Abstract In contrast to the traditional mechanism of drug action that relies on reversible, noncovalent interaction a ligand with its biological target, targeted covalent inhibitor (TCI) is designed such initial, reversible association followed by formation bond between an electrophile and nucleophilic center in protein. Although this approach offers variety potential benefits (high potency extended duration action), concerns over possible toxicological consequences protein haptenization have hindered development TCI concept. Recently, approaches mitigate risk serious adverse reactions new class agent emerged, thus stimulating interest field leading authorization first cadre TCIs be marketed. The rapidly gaining acceptance as valuable tool discovery, poised make major impact design enzyme inhibitors receptor modulators.

Language: Английский

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Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

Journal of Medicinal Chemistry, Journal Year: 2016, Volume and Issue: 60(3), P. 839 - 885

Published: Dec. 20, 2016

Although Michael acceptors display a potent and broad spectrum of bioactivity, they have largely been ignored in drug discovery because their presumed indiscriminate reactivity. As such, dearth information exists relevant to the thiol reactivity natural products analogues possessing this moiety. In midst recently approved acrylamide-containing drugs, it is clear that good understanding hetero-Michael addition reaction relative reactivities biological thiols with under physiological conditions needed for design use these compounds as tools potential therapeutics. This Perspective provides will contribute understanding, such kinetics reactions, bioactivities, well steric electronic factors influence electrophilicity reversibility acceptors. focused on α,β-unsaturated carbonyls given preponderance bioactive products.

Language: Английский

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Prolonged and tunable residence time using reversible covalent kinase inhibitors

Nature Chemical Biology, Journal Year: 2015, Volume and Issue: 11(7), P. 525 - 531

Published: May 25, 2015

Language: Английский

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Structure-based design of targeted covalent inhibitors

Chemical Society Reviews, Journal Year: 2018, Volume and Issue: 47(11), P. 3816 - 3830

Published: Jan. 1, 2018

Covalent inhibition is a rapidly growing discipline within drug discovery.

Language: Английский

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CavityPlus: a web server for protein cavity detection with pharmacophore modelling, allosteric site identification and covalent ligand binding ability prediction

Nucleic Acids Research, Journal Year: 2018, Volume and Issue: 46(W1), P. W374 - W379

Published: April 30, 2018

CavityPlus is a web server that offers protein cavity detection and various functional analyses. Using three-dimensional structural information as the input, applies CAVITY to detect potential binding sites on surface of given structure rank them based ligandability druggability scores. These can be further analysed using three submodules, CavPharmer, CorrSite, CovCys. CavPharmer uses receptor-based pharmacophore modelling program, Pocket, automatically extract features within cavities. CorrSite identifies allosteric ligand-binding motion correlation analyses between CovCys detects druggable cysteine residues, which especially useful identify novel for designing covalent ligands. Overall, provides an integrated platform analysing comprehensive properties Such are many aspects drug design discovery, including target selection identification, virtual screening, de novo design, covalent-binding design. The freely available at http://repharma.pku.edu.cn/cavityplus or http://www.pkumdl.cn/cavityplus.

Language: Английский

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