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

## TL;DR

Researchers found new compounds that inhibit a key malaria enzyme, offering potential for new antimalarial drugs.

## Contribution

Identification of salicylic acid derivatives as potent inhibitors of Plasmodium falciparum threonyl tRNA-synthetase via virtual screening and structural analysis.

## Key findings

- Nine low micromolar PfThrRS inhibitors were identified through virtual screening and FRET assay.
- Salicylic acid-based compound showed high ligand efficiency and was optimized into 146 analogues.
- Crystal structure of a salicylic acid-EcThrRS complex guided hit-to-lead optimization.

## 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.