8QIC

Structure-based identification of salicylic acid derivatives as malarial threonyl tRNA-synthetase inhibitors

8QIC の概要

• エントリーDOI: 10.2210/pdb8qic/pdb
• 分子名称: Threonine--tRNA ligase, 2-oxidanyl-5-[[4-(phenylmethyl)phenyl]sulfamoyl]benzoic acid, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: threonyl trna-synthetase, malaria, plasmodium falciparum, salicylic acid, ligase
• 由来する生物種: Escherichia coli O8
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 94402.00

構造登録者

Rodriguez, J.A.,Parisini, E. (登録日: 2023-09-13, 公開日: 2024-04-10)

主引用文献

Bobrovs, R.,Bolsakova, J.,Buitrago, J.A.R.,Varaceva, L.,Skvorcova, M.,Kanepe, I.,Rudnickiha, A.,Parisini, E.,Jirgensons, A.
Structure-based identification of salicylic acid derivatives as malarial threonyl tRNA-synthetase inhibitors.
Plos One, 19:e0296995-e0296995, 2024

PubMed Abstract: Emerging resistance to existing antimalarial drugs drives the search for new antimalarials, and protein translation is a promising pathway to target. Threonyl t-RNA synthetase (ThrRS) is one of the enzymes involved in this pathway, and it has been validated as an anti-malarial drug target. Here, we present 9 structurally diverse low micromolar Plasmodium falciparum ThrRS inhibitors that were identified using high-throughput virtual screening (HTVS) and were verified in a FRET enzymatic assay. Salicylic acid-based compound (LE = 0.34) was selected as a most perspective hit and was subjected to hit-to-lead optimisation. A total of 146 hit analogues were synthesised or obtained from commercial vendors and were tested. Structure-activity relationship study was supported by the crystal structure of the complex of a salicylic acid analogue with a close homologue of the plasmodium target, E. coli ThrRS (EcThrRS). Despite the availability of structural information, the hit identified via virtual screening remained one of the most potent PfThrRS inhibitors within this series. However, the compounds presented herein provide novel scaffolds for ThrRS inhibitors, which could serve as starting points for further medicinal chemistry projects targeting ThrRSs or structurally similar enzymes.

PubMed: 38558084
DOI: 10.1371/journal.pone.0296995

実験手法

X-RAY DIFFRACTION (2.5 Å)