{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:18:33Z","timestamp":1789445913798,"version":"build-2803163510"},"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008530","name":"ERDF","doi-asserted-by":"crossref","award":["1.1.1.1\/19\/A\/019"],"award-info":[{"award-number":["1.1.1.1\/19\/A\/019"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>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 <jats:italic>Plasmodium falciparum<\/jats:italic> 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, <jats:italic>E<\/jats:italic>. <jats:italic>coli<\/jats:italic> ThrRS (<jats:italic>Ec<\/jats:italic>ThrRS). Despite the availability of structural information, the hit identified via virtual screening remained one of the most potent <jats:italic>Pf<\/jats:italic>ThrRS 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.<\/jats:p>","DOI":"10.1371\/journal.pone.0296995","type":"journal-article","created":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T17:36:30Z","timestamp":1711992990000},"page":"e0296995","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Structure-based identification of salicylic acid derivatives as malarial threonyl tRNA-synthetase inhibitors"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0221-8658","authenticated-orcid":true,"given":"Raitis","family":"Bobrovs","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jekaterina","family":"Bolsakova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jhon Alexander Rodriguez","family":"Buitrago","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larisa","family":"Varaceva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marija","family":"Skvorcova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iveta","family":"Kanepe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1838-5716","authenticated-orcid":true,"given":"Anastasija","family":"Rudnickiha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Parisini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aigars","family":"Jirgensons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,4,1]]},"reference":[{"key":"pone.0296995.ref001","author":"World Health Organization","year":"2022","journal-title":"World malaria report 2022"},{"key":"pone.0296995.ref002","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1038\/nrd2972","article-title":"New medicines to improve control and contribute to the eradication of malaria","author":"TNC Wells","year":"2009","journal-title":"Nature Reviews Drug Discovery"},{"key":"pone.0296995.ref003","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.ijbiomac.2017.12.157","article-title":"Aminoacyl-tRNA synthetases: Structure, function, and drug discovery","volume":"111","author":"V Rajendran","year":"2018","journal-title":"Int J Biol Macromol"},{"key":"pone.0296995.ref004","doi-asserted-by":"crossref","first-page":"5227","DOI":"10.1016\/j.ejmech.2011.08.049","article-title":"Aminoacyl-tRNA synthetase inhibitors as potential antibiotics","volume":"46","author":"GHM Vondenhoff","year":"2011","journal-title":"Eur J Med Chem"},{"key":"pone.0296995.ref005","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/s41573-019-0026-3","article-title":"Aminoacyl-tRNA synthetases as therapeutic targets.","volume":"18","author":"NH Kwon","year":"2019","journal-title":"Nat Rev Drug Discov"},{"key":"pone.0296995.ref006","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.3390\/ijms22041750","article-title":"Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery.","volume":"22","author":"L Pang","year":"2021","journal-title":"Int J Mol Sci."},{"key":"pone.0296995.ref007","doi-asserted-by":"crossref","first-page":"5365","DOI":"10.1074\/jbc.REV118.002956","article-title":"Progress and challenges in aminoacyl-tRNA synthetase-based therapeutics","volume":"294","author":"CS Francklyn","year":"2019","journal-title":"Journal of Biological Chemistry"},{"key":"pone.0296995.ref008","first-page":"1625","article-title":"Recent Development of Aminoacyl-tRNA Synthetase Inhibitors for Human Diseases","volume":"10","author":"S-H Kim","year":"2020","journal-title":"A Future Perspective. 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