{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T18:44:48Z","timestamp":1782758688620,"version":"3.54.5"},"reference-count":68,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,6,21]],"date-time":"2023-06-21T00:00:00Z","timestamp":1687305600000},"content-version":"vor","delay-in-days":171,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007648","name":"Durban University of Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007648","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["BioMed Research International"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:p>Malaria is a devastating disease, and its management is only achieved through chemotherapy. However, resistance to available medication is still a challenge; therefore, there is an urgent need for the discovery and development of therapeutics with a novel mechanism of action to counter the resistance scourge consistent with the currently available antimalarials. Recently, plasmepsin V was validated as a therapeutic target for the treatment of malaria. The pepsin\u2010like aspartic protease anchored in the endoplasmic reticulum is responsible for the trafficking of parasite\u2010derived proteins to the erythrocytic surface of the host cells. In this study, a small library of compounds was preliminarily screened <jats:italic>in vitro<\/jats:italic> to identify novel modulators of <jats:italic>Plasmodium falciparum<\/jats:italic> plasmepsin V (<jats:italic>Pf<\/jats:italic>PMV). The results obtained revealed kaempferol, quercetin, and shikonin as possible <jats:italic>Pf<\/jats:italic>PMV inhibitors, and these compounds were subsequently probed for their inhibitory potentials using <jats:italic>in vitro<\/jats:italic> and <jats:italic>in silico<\/jats:italic> methods. Kaempferol and shikonin noncompetitively and competitively inhibited the specific activity of <jats:italic>Pf<\/jats:italic>PMV <jats:italic>in vitro<\/jats:italic> with IC<jats:sub>50<\/jats:sub> values of 22.4 and 43.34\u2009<jats:italic>\u03bc<\/jats:italic>M, respectively, relative to 62.6\u2009<jats:italic>\u03bc<\/jats:italic>M obtained for pepstatin, a known aspartic protease inhibitor. Further insight into the structure\u2010activity relationship of the compounds through a 100\u2009ns molecular dynamic (MD) simulation showed that all the test compounds had a significant affinity for <jats:italic>Pf<\/jats:italic>PMV, with quercetin (\u201036.56\u2009kcal\/mol) being the most prominent metabolite displaying comparable activity to pepstatin (\u201035.72\u2009kcal\/mol). This observation was further supported by the compactness and flexibility of the resulting complexes where the compounds do not compromise the structural integrity of <jats:italic>Pf<\/jats:italic>PMV but rather stabilized and interacted with the active site amino acid residues critical to <jats:italic>Pf<\/jats:italic>PMV modulation. Considering the findings in this study, quercetin, kaempferol, and shikonin could be proposed as novel aspartic protease inhibitors worthy of further investigation in the treatment of malaria.<\/jats:p>","DOI":"10.1155\/2023\/6229503","type":"journal-article","created":{"date-parts":[[2023,6,21]],"date-time":"2023-06-21T20:21:54Z","timestamp":1687378914000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Bioprospection of Selected Plant Secondary Metabolites as Modulators of the Proteolytic Activity of <i>Plasmodium falciparum<\/i> Plasmepsin V"],"prefix":"10.1155","volume":"2023","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3660-0916","authenticated-orcid":false,"given":"Abdulhakeem Olarewaju","family":"Sulyman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oluwapelumi Oluwaseun","family":"Aje","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel Oladipo","family":"Ajani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rukayat Abiola","family":"Abdulsalam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1125-0107","authenticated-orcid":false,"given":"Fatai Oladunni","family":"Balogun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7209-9220","authenticated-orcid":false,"given":"Saheed","family":"Sabiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,6,21]]},"reference":[{"key":"e_1_2_9_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.idc.2012.03.010"},{"key":"e_1_2_9_2_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-022-04130-9"},{"key":"e_1_2_9_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph19063544"},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.3390\/biology11030409"},{"key":"e_1_2_9_5_2","volume-title":"World Malaria Report","author":"WHO","year":"2021"},{"key":"e_1_2_9_6_2","unstructured":"KingP. 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