Atomic Resolution Analyses of Isocoumarin Derivatives for Inhibition of Lysyl-tRNA Synthetase
| Autor: | Pengfei Fang, Wei Li, Jintong Zhou, Zhoufei Hei, Li Zheng, Jing Wang, Biao Yu |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Lysine-tRNA Ligase
0301 basic medicine Double bond Stereochemistry Plasmodium falciparum Crystallography X-Ray 01 natural sciences Biochemistry Chemical synthesis Antimalarials 03 medical and health sciences chemistry.chemical_compound Molecular recognition Catalytic Domain Moiety Enzyme Inhibitors chemistry.chemical_classification 010405 organic chemistry Chemistry General Medicine Antiparasitic agent 0104 chemical sciences Isocoumarin 030104 developmental biology Isocoumarins Lactam Molecular Medicine Lactone Protein Binding |
| Zdroj: | ACS Chemical Biology. 15:1016-1025 |
| ISSN: | 1554-8937 1554-8929 |
| Popis: | Aminoacyl-tRNA synthetases, the essential enzyme family for protein translation, are attractive targets for developing antibacterial, antifungal, and antiparasitic agents and for treating other human diseases. The antimalarial natural product cladosporin was discovered recently as a novel lysyl-tRNA synthetase (LysRS) specific inhibitor. Here, we report a thorough analysis of cladosporin derivatives using chemical synthesis, biophysical, and biochemical experiments. A series of isocoumarin derivatives with only one nonhydrogen atom/bond change per compound was synthesized. These changes include replacements of methyltetrahydropyran moiety by methylcyclohexane or cyclohexane, lactone by lactam, hydroxyl groups by methoxyl groups, and dismission of the chiral center at C3 with a Δ3,4 double bond. We evaluated these compounds by thermal shift assays and enzymatic experiments and further studied their molecular recognition by the Plasmodium falciparum LysRS through total five high-resolution crystal structures. Our results showed that the methyltetrahydropyran moiety of cladosporin could be replaced by a more stable methylcyclohexane without reducing binding ability. Removing the methyl group from the methylcyclohexane moiety slightly decreased the interaction with LysRS. Besides, the replacement with a lactam group or a conjugated Δ3,4 double bond within the scaffold could be two more options to optimize the compound. Lastly, the two phenolic hydroxyl groups were critical for the compounds to bind LysRS. The detailed analyses at atomic resolution in this study provide a foundation for the further development of new antibiotics from cladosporin derivatives. |
| Databáze: | OpenAIRE |
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