Covalent fragment libraries in drug discovery

Fragment-based covalent ligand discovery

“…1). We would like to note that several excellent reviews focusing on covalent fragment library design have recently been published, 1,2,[17][18][19] and we will not comment on this here.…”

Library Design Strategies To Accelerate Fragment‐Based Drug Discovery

“…[67][68][69] However,r ecent reports have shown that screening of electrophilicf ragments mays erve as an efficient toolf or covalentligand discovery. [70] Similar to reversiblet ethering, screening of electrophilic fragments can advantageously be performed with mixtures and analyzed by means of intact-protein MS. [71,72] To ensure that hits represent the best bindingf ragments rather than the most reactive ones, cocktails should be comprised of fragments with comparable electrophilicity.Anumber of electrophilic warheads can be implemented fort his approach, and an interestings tudy of the promiscuity and selectivityo fs uch electrophiles has been published by Klein and co-workers. [73] For cysteine-containingt argets,c hloroacetamides andM ichael acceptors are predominantly used.…”

Multiparameter Kinetic Analysis for Covalent Fragment Optimization by Using Quantitative Irreversible Tethering (qIT)

“…Moreover, covalent binding of the target expedites chemical biology experiments, such as activity‐based protein profiling and fluorescence microscopy, that are invaluable in their ability to complement genetic studies [5] . Covalent fragment libraries are typically comprised of low‐molecular‐weight bifunctional molecules, carrying amino acid‐reactive warheads, such as Michael acceptors and electrophilic heterocycles, and an unreactive specificity element, which directs the warhead selectively to the target of interest [6,7] . Libraries are designed to maximize the chemical diversity of the specificity elements, using one or more class of warhead, and may include a flexible linker to target distal amino acids [6,8,9] .…”

“…[5] Covalent fragment libraries are typically comprised of low-molecularweight bifunctional molecules, carrying amino acid-reactive warheads, such as Michael acceptors and electrophilic heterocycles, and an unreactive specificity element, which directs the warhead selectively to the target of interest. [6,7] Libraries are designed to maximize the chemical diversity of the specificity elements, using one or more class of warhead, and may include a flexible linker to target distal amino acids. [6,8,9] Target-directed screening against recombinant proteins is generally achieved by intact protein mass spectrometry or fluorescence-based tethering techniques to detect hit chemical starting points.…”

“…[6,7] Libraries are designed to maximize the chemical diversity of the specificity elements, using one or more class of warhead, and may include a flexible linker to target distal amino acids. [6,8,9] Target-directed screening against recombinant proteins is generally achieved by intact protein mass spectrometry or fluorescence-based tethering techniques to detect hit chemical starting points. [10][11][12] An alternative strategy is to use cell-based screening of covalent fragments to identify new chemical starting points and/or protein targets through activity-based protein profiling strategies.…”