An update on the discovery and development of reversible covalent inhibitors

Medicinal Chemistry Research, Journal Year: 2023, Volume and Issue: 32(6), P. 1039 - 1062

Published: April 29, 2023

Language: Английский

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Room-temperature crystallography reveals altered binding of small-molecule fragments to PTP1B

eLife, Journal Year: 2023, Volume and Issue: 12

Published: March 6, 2023

Much of our current understanding how small-molecule ligands interact with proteins stems from X-ray crystal structures determined at cryogenic (cryo) temperature. For alone, room-temperature (RT) crystallography can reveal previously hidden, biologically relevant alternate conformations. However, less is understood about RT may impact the conformational landscapes protein-ligand complexes. Previously, we showed that fragments cluster in putative allosteric sites using a cryo crystallographic screen therapeutic target PTP1B (Keedy et al., 2018). Here, have performed two screens many same fragments, representing largest diverse library to date, and enabling direct interrogation effect data collection temperature on interactions. We show RT, fewer bind, often more weakly – but variety temperature-dependent differences, including unique binding poses, changes solvation, new sites, distinct protein responses. Overall, this work suggests vast body existing cryo-temperature provide an incomplete picture, highlights potential help complete picture by revealing modes systems. Our results inspire future use interrogate roles ensembles biological function.

Language: Английский

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Drug discovery considerations in the development of covalent inhibitors

Bioorganic & Medicinal Chemistry Letters, Journal Year: 2013, Volume and Issue: 24(1), P. 33 - 39

Published: Oct. 10, 2013

In recent years, the number of drug candidates with a covalent mechanism action progressing through clinical trials or being approved by FDA has increased significantly. And as interest in inhibitors increased, technical challenges for characterizing and optimizing these have become evident. A new tools been developed to aid this process, but not gained wide-spread use. This review will highlight methods useful prosecuting inhibitor discovery programs.

Language: Английский

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A Fragment-Based Method to Discover Irreversible Covalent Inhibitors of Cysteine Proteases

Journal of Medicinal Chemistry, Journal Year: 2014, Volume and Issue: 57(11), P. 4969 - 4974

Published: May 28, 2014

A novel fragment-based drug discovery approach is reported which irreversibly tethers drug-like fragments to catalytic cysteines. We attached an electrophile 100 without significant alterations in the reactivity of electrophile. mass spectrometry assay discovered three nonpeptidic inhibitors cysteine protease papain. The identified compounds display characteristics irreversible inhibitors. tethering system also displays specificity: papain did not covalently react with UbcH7, USP08, or GST-tagged human rhinovirus 3C protease.

Language: Английский

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Current perspectives in fragment-based lead discovery (FBLD)

Essays in Biochemistry, Journal Year: 2017, Volume and Issue: 61(5), P. 453 - 464

Published: Nov. 8, 2017

It is over 20 years since the first fragment-based discovery projects were disclosed. The methods are now mature for most ‘conventional’ targets in drug such as enzymes (kinases and proteases) but there has also been growing success on more challenging targets, disruption of protein–protein interactions. main application to identify tractable chemical startpoints that non-covalently modulate activity a biological molecule. In this essay, we overview current practice discuss how they have had an impact lead – generating large number fragment-derived compounds clinical trials two medicines treating patients. addition, some recent applications biology providing tools investigate molecules, mechanisms systems.

Language: Английский

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