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

Autor: Bobrovs R; Latvian Institute of Organic Synthesis, Riga, Latvia., Bolsakova J; Latvian Institute of Organic Synthesis, Riga, Latvia., Buitrago JAR; Latvian Institute of Organic Synthesis, Riga, Latvia., Varaceva L; Latvian Institute of Organic Synthesis, Riga, Latvia., Skvorcova M; Latvian Institute of Organic Synthesis, Riga, Latvia., Kanepe I; Latvian Institute of Organic Synthesis, Riga, Latvia., Rudnickiha A; Latvian Institute of Organic Synthesis, Riga, Latvia., Parisini E; Latvian Institute of Organic Synthesis, Riga, Latvia.; Department of Chemistry 'G. Ciamician', University of Bologna, Bologna, Italy., Jirgensons A; Latvian Institute of Organic Synthesis, Riga, Latvia.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2024 Apr 01; Vol. 19 (4), pp. e0296995. Date of Electronic Publication: 2024 Apr 01 (Print Publication: 2024).
DOI: 10.1371/journal.pone.0296995
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Bobrovs et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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