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Repurposing existing drugs and active compounds offers a viable pathway to develop new therapies for various diseases. By leveraging publicly available biomedical information, it is possible to predict compounds\u2019 activity and identify their potential targets across diverse organisms. In this study, we aimed to assess the antiplasmodial activity of compounds from the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library using in vitro and bioinformatics approaches. We assessed the in vitro antiplasmodial activity of the compounds using blood-stage and liver-stage drug susceptibility assays. We used protein sequences of known targets of the ReFRAME compounds with high antiplasmodial activity (EC<jats:sub>50<\/jats:sub>\u2009&lt;\u200910\u00a0uM) to conduct a protein-pairwise search to identify similar <jats:italic>Plasmodium falciparum<\/jats:italic> 3D7 proteins (from PlasmoDB) using NCBI protein BLAST. We further assessed the association between the compounds' in vitro antiplasmodial activity and level of similarity between their known and predicted <jats:italic>P. falciparum<\/jats:italic> target proteins using simple linear regression analyses. BLAST analyses revealed 735 <jats:italic>P. falciparum<\/jats:italic> proteins that were similar to the 226 known protein targets associated with the ReFRAME compounds. Antiplasmodial activity of the compounds was positively associated with the degree of similarity between the compounds\u2019 known targets and predicted <jats:italic>P. falciparum<\/jats:italic> protein targets (percentage identity, E value, and bit score), the number of the predicted <jats:italic>P. falciparum<\/jats:italic> targets, and their respective mutagenesis index and fitness scores (R<jats:sup>2<\/jats:sup> between 0.066 and 0.92, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). Compounds predicted to target essential <jats:italic>P. falciparum<\/jats:italic> proteins or those with a druggability index of 1 showed the highest antiplasmodial activity.<\/jats:p>","DOI":"10.1186\/s13321-024-00856-7","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T11:01:57Z","timestamp":1717412517000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Protein target similarity is positive predictor of in vitro antipathogenic activity: a drug repurposing strategy for Plasmodium falciparum"],"prefix":"10.1186","volume":"16","author":[{"given":"Reagan M.","family":"Mogire","sequence":"first","affiliation":[]},{"given":"Silviane A.","family":"Miruka","sequence":"additional","affiliation":[]},{"given":"Dennis W.","family":"Juma","sequence":"additional","affiliation":[]},{"given":"Case W.","family":"McNamara","sequence":"additional","affiliation":[]},{"given":"Ben","family":"Andagalu","sequence":"additional","affiliation":[]},{"given":"Jeremy N.","family":"Burrows","sequence":"additional","affiliation":[]},{"given":"Elodie","family":"Chenu","sequence":"additional","affiliation":[]},{"given":"James","family":"Duffy","sequence":"additional","affiliation":[]},{"given":"Bernhards R.","family":"Ogutu","sequence":"additional","affiliation":[]},{"given":"Hoseah M.","family":"Akala","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2024,5,30]]},"reference":[{"issue":"2","key":"856_CR1","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/S0167-6296(02)00126-1","volume":"22","author":"JA DiMasi","year":"2003","unstructured":"DiMasi JA, Hansen RW, Grabowski HG (2003) The price of innovation: new estimates of drug development costs. 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