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Since ancient times, plants have served as a primary source of novel pharmacologically active compounds for drug development. Therefore, this study aimed to explore the antiplasmodial properties of pentacyclic triterpenes isolated from <jats:italic>Ziziphus mucronata<\/jats:italic> bark, with an emphasis on their mechanism of action. Dichloromethane and ethyl acetate extracts of the stem bark were subjected to silica gel column chromatography, which led to the isolation of three known triterpenoids: betulinic acid, methyl betulinate, and lupeol. The compounds were then evaluated for antiplasmodial activity against <jats:italic>Plasmodium falciparum<\/jats:italic> NF54 strains using the <jats:italic>Plasmodium<\/jats:italic> lactate dehydrogenase (pLDH) assay. In silico evaluation of the isolated compounds was conducted through molecular docking and further validated with in vitro experiments against a purified protein target, <jats:italic>Plasmodium falciparum<\/jats:italic> hypoxanthine\u2013guanine\u2013xanthine phosphoribosyltransferase (<jats:italic>Pf<\/jats:italic>HGXPRT). Betulinic acid, methyl betulinate, and lupeol exhibited potent antiplasmodial activities with IC<jats:sub>50<\/jats:sub> values of 20, 10.11, and 7.56\u00a0\u00b5g\/mL, respectively. Lupeol exhibited the highest binding energy of\u2009\u2212\u20097.6\u00a0kcal\/mol. Differential scanning fluorimetry revealed that lupeol decreases the <jats:italic>T<\/jats:italic>\n            <jats:sub>m<\/jats:sub> of <jats:italic>Pf<\/jats:italic>HGXPRT, thus decreasing the protein\u2019s thermal stability. At high concentrations, lupeol also increased protein absorbance, indicating the detection of hydrophobic amino acids and protein unfolding. This study proves that <jats:italic>Z. mucronata<\/jats:italic> could serve as a reservoir of effective agents for treating malaria, while also scientifically validating its use in traditional medicine. However, further experimental studies are required to substantiate its relevant therapeutic effects.<\/jats:p>","DOI":"10.1007\/s00210-024-03611-9","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T09:26:36Z","timestamp":1732008396000},"page":"5453-5463","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Antiplasmodial potential of compounds isolated from Ziziphus mucronata and their binding to Plasmodium falciparum HGXPRT using biophysical and molecular docking studies"],"prefix":"10.1007","volume":"398","author":[{"given":"Kgaugelo J.","family":"Masia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ndumiso N.","family":"Mhlongo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ofentse J.","family":"Pooe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed A.","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abidemi P.","family":"Kappo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mthokozisi B. 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