Protein-Directed Dynamic Combinatorial Chemistry: A Guide to Protein Ligand and Inhibitor Discovery

Abstract

Protein-directed dynamic combinatorial chemistry is an emerging technique for efficient discovery of novel chemical structures for binding to a target protein. Typically, this method relies on a library of small molecules that react reversibly with each other to generate a combinatorial library. The components in the combinatorial library are at equilibrium with each other under thermodynamic control. When a protein is added to the equilibrium mixture, and if the protein interacts with any components of the combinatorial library, the position of the equilibrium will shift and those components that interact with the protein will be amplified, which can then be identified by a suitable biophysical technique. Such information is useful as a starting point to guide further organic synthesis of novel protein ligands and enzyme inhibitors. This review uses literature examples to discuss the practicalities of applying this method to inhibitor discovery, in particular, the set-up of the combinatorial library, the reversible reactions that may be employed, and the choice of detection methods to screen protein ligands from a mixture of reversibly forming molecules.

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

“…Most studies in the field have used liquid chromatography,usually in combination with mass spectrometry (LC-MS). [13,[21][22][23][24][25][26][27][28][29][30] In some examples,s pecific methods of NMR spectroscopy were developed. [31][32][33][34][35][36] In addition, fragment ligations have been studied by X-ray crystallography.…”

“…[1,10,[43][44][45][46][47][48] Thed etection of fragment ligation products by LC-MS has become substantially easier over the last two decades because of the rapid development of this method in terms of chromatographic separation and the sensitivity of mass detectors. [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.…”

Multiprotein Dynamic Combinatorial Chemistry: A Strategy for the Simultaneous Discovery of Subfamily‐Selective Inhibitors for Nucleic Acid Demethylases FTO and ALKBH3

“…Dynamic combinatorial chemistry (DCC) is a powerful supramolecular approach for discovering ligands for biological targets. The idea was first independently conceived and developed by the Sanders and Lehn groups (for excellent reviews, see Refs ) . In the DCC method, simple building blocks are linked together by reversible covalent chemistry to generate dynamic libraries of structures.…”

“…The idea was first independently conceived and developed by the Sanders and Lehn groups (for excellent reviews, see Refs [1][2][3][4][5][6][7][8][9][10]). [1][2][3][4][5][6][7][8][9][10] In the DCC method, simple building blocks are linked togetherb yreversible covalentc hemistry to generated ynamic libraries of structures. Because of the reversible nature of these libraries, they are highly responsive to external influence, such that the introduction of at emplate triggers the rapid structural adaptation of librarym embers, which results in the assembly of structures that are highly complementaryt ot he template.…”

Dynamic Combinatorial Chemistry to Identify Binders of ThiT, an S‐Component of the Energy‐Coupling Factor Transporter for Thiamine

“…Over the past 20 years, DCC has been successfully applied in medicinal chemistry and chemicalb iology for the discovery of binderst oD NA,R NA and protein targets. [1][2][3] The DCC technique involves the generation of al ibraryo fc ompounds by reversible reactiono fd ifferent buildingb locks. The main advantage of DCC is that several potential ligands for ap rotein can be screeneds imultaneously, avoidingt he individual synthesis, purification and biochemical evaluation of every member of the dynamic combinatorial library (DCL).…”