7BZJ

The Discovery of Benzhydrol-Oxaborole Hybrid Derivatives as Leucyl-tRNA Synthetase Inhibitors

7BZJ の概要

• エントリーDOI: 10.2210/pdb7bzj/pdb
• 分子名称: Leucine--tRNA ligase, [(1~{R},5~{R},6~{S},8~{R})-8-(6-aminopurin-9-yl)-4'-[(~{R})-oxidanyl-[4-(2-oxidanylidenepropylsulfanyl)phenyl]methyl]spiro[2,4,7-trioxa-3-boranuidabicyclo[3.3.0]octane-3,7'-7-boranuidabicyclo[4.3.0]nona-1(6),2,4-triene]-6-yl]methoxy-tris(oxidanyl)phosphanium (3 entities in total)
• 機能のキーワード: leucyl-trna synthetase, pneumonia, rna binding protein-inhibitor complex, rna binding protein/inhibitor
• 由来する生物種: Streptococcus pneumoniae (strain ATCC 700669 / Spain 23F-1)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 21746.89

構造登録者

Liu, R.J.,Li, H.,Wang, E.D.,Zhou, H. (登録日: 2020-04-28, 公開日: 2020-12-09, 最終更新日: 2023-11-29)

主引用文献

Hao, G.,Li, H.,Yang, F.,Dong, D.,Li, Z.,Ding, Y.,Pan, W.,Wang, E.,Liu, R.,Zhou, H.
Discovery of benzhydrol-oxaborole derivatives as Streptococcus pneumoniae leucyl-tRNA synthetase inhibitors.
Bioorg.Med.Chem., 29:115871-115871, 2021

PubMed Abstract: Pneumonia caused by bacterium S. pneumoniae is a severe acute respiratory infectious disease with high morbidity and mortality, especially for children and immunity-compromised patients. The emergence of multidrug-resistant S. pneumoniae also presents a challenge to human health. Leucyl-tRNA synthetase (LeuRS) catalyzes the attachment of l-leucine to tRNA, which plays an essential role in protein translation and is considered an attractive antimicrobial drug target. In the present work, benzhydrol-oxaborole hybrid compounds were designed and synthesized as inhibitors of S. pneumoniae LeuRS. Exploration of the phenyl ring near Lysine 389 eventually yielded compounds 46 and 54 with submicromolar inhibitory potency. The co-crystal of compound 54 in the editing domain pocket of SpLeuRS was obtained and confirmed the formation of an additional hydrogen bond between the carbonyl of 54 and Lysine 389. It also showed anti-pneumococcal activity in vitro. The structure-activity relationship was discussed. This work will provide an essential foundation for the further development of anti-pneumococcal agents by targeting LeuRS.

PubMed: 33221064
DOI: 10.1016/j.bmc.2020.115871

実験手法

X-RAY DIFFRACTION (2 Å)