Multiprotein Dynamic Combinatorial Chemistry: A Strategy for the Simultaneous Discovery of Subfamily-Selective Inhibitors for Nucleic Acid Demethylases FTO and ALKBH3
| Autor: | Mohua Das, Kendra H. Q. Wong, Fransisca Prasetya, Tianming Yang, Jinghua Dong, Esther C. Y. Woon, Adeline Cheong, Yiming Xie |
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| Rok vydání: | 2018 |
| Předmět: |
Oxidoreductases
O-Demethylating Protein Denaturation Subfamily Recombinant Fusion Proteins Supramolecular chemistry Alpha-Ketoglutarate-Dependent Dioxygenase FTO Computational biology 010402 general chemistry Ligands Protein Engineering 01 natural sciences Biochemistry Catalysis Protein Structure Secondary Discriminatory power Dynamic combinatorial chemistry Combinatorial Chemistry Techniques Humans Transition Temperature Fluorometry Enzyme Inhibitors chemistry.chemical_classification Molecular Structure 010405 organic chemistry Drug discovery Chemistry Biomolecule Organic Chemistry Hydrazones AlkB Homolog 5 RNA Demethylase General Chemistry 0104 chemical sciences Highly sensitive Kinetics Nucleic acid AlkB Homolog 3 Alpha-Ketoglutarate-Dependent Dioxygenase Peptides |
| Zdroj: | Chemistry, an Asian journal. 13(19) |
| ISSN: | 1861-471X |
| Popis: | Dynamic combinatorial chemistry (DCC) is a powerful supramolecular approach for discovering ligands for biomolecules. To date, most, if not all, biologically templated DCC systems employ only a single biomolecule to direct the self‐assembly process. To expand the scope of DCC, herein, a novel multiprotein DCC strategy has been developed that combines the discriminatory power of a zwitterionic “thermal tag” with the sensitivity of differential scanning fluorimetry. This strategy is highly sensitive and could differentiate the binding of ligands to structurally similar subfamily members. Through this strategy, it was possible to simultaneously identify subfamily‐selective probes against two clinically important epigenetic enzymes: FTO (7 ; IC_{50} = 2.6 μm ) and ALKBH3 (8 ; IC_{50} = 3.7 μm ). To date, this is the first report of a subfamily‐selective ALKBH3 inhibitor. The developed strategy could, in principle, be adapted to a broad range of proteins; thus it is of broad scientific interest. |
| Databáze: | OpenAIRE |
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