Kinetic Target-Guided Synthesis in Drug Discovery and Chemical Biology: A Comprehensive Facts and Figures Survey

Abstract

For the last 15 years, kinetic target-guided syntheses, including in situ click chemistry, have been used as alternative methods to find ligands to therapeutically relevant proteins. In this review, a comprehensive survey of biological targets used in kinetic target-guided synthesis covers historical and recent examples. The chemical reactions employed and practical aspects, including controls, library sizes and product detection, are presented. A particular focus is on the reagents and warhead selection and design with a critical overview of the challenges encountered. As protein supply remains a key success factor, it appears that increased efforts should be taken toward miniaturization in order to expand the scope of this strategy and qualify it as a fully fledged drug discovery tool.

Protein‐Templated Fragment Ligations—From Molecular Recognition to Drug Discovery

“…[13,[25][26][27][28] Not only detection but also quantification and structure elucidation of ligation products is facilitated by using extracted-ion or single-ion chromatography and MS-MS techniques.S ome limitations remain, however.A s chromatographic separation takes some time,L C-MS detection is best suited for irreversible or quasi-irreversible ligation reactions. [15,49] In the case of reversibly formed ligation products,t heir chemical fixation by ac hemical reaction or ap Hs hift can be an option. This strategy was followed, for example,i nt he seminal report by Huc and Lehn on "virtual chemical libraries", in which the unstable imine ligation products were converted into stable amines by chemical reduction during the ligation reaction.…”

“…In Section 4wewill give an overview of the chemical reactions used so far in templated ligations and also discuss possible future extensions of this reaction set. Reversible reactions, which have been studied in the context of dynamic covalent chemistry [7][8][9][10][11][12][13][14] and irreversible reactions,also denominated as target-guided synthesis (TGS), [15] are treated together,a sb oth reaction categories deliver examples of templated fragment ligations and in many cases it is difficult to categorize one reaction unambiguously.R epresentative recent applications of templated ligations in fragment-based drug discovery are reported in Section 5, thus demonstrating how far the method has developed to date.F inally,i n Section 6w ew ill discuss the current state of protein-templated fragment ligations,considering the strengths of this method and the requirements for it to succeed. Thec omplementarity of the method with classical ligand screening and fragment-based methods will be considered, thereby leading to an outlook on the relevance and further development of proteintemplated fragment ligations for future drug discovery.…”

Drug Design Concepts for LSD1‐Selective Inhibitors

“…Target‐guided synthesis (TGS) is a method that allows target enzymes to synthesize their own inhibitors . The inhibitors identified by TGS are expected to show strong activity and high target selectivity because they are synthesized by a specific reaction (catalytic reaction in the case of LSD1 inhibitors) and/or in specific pockets of a target enzyme.…”

Optimized Inhibitors of MDM2 via an Attempted Protein‐Templated Reductive Amination

“…[1,2,[6][7][8][9][10][11][12][13][14][15][16][17][18][19] The most widely used reaction is the Huisgen 1,3-dipolar cycloaddition of azides and alkynes and most work in KTGS focuses on acetylcholine esterase (AChE) from various species, although different reactions and targets have been explored. [2,3] Protein-protein interactions (PPIs) are involved in many biological functions, such as intercellular communication and apoptosis. Targeting PPIs using small molecules is considered challenging given the flatness of the interface, a lack of small-molecule starting points for the future design and the difficulties in distinguishing real from artefactual binding.…”