{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T16:10:43Z","timestamp":1789834243787,"version":"4.0.1"},"reference-count":47,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,1,4]],"date-time":"2022-01-04T00:00:00Z","timestamp":1641254400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chemistry &amp; Biodiversity"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Multidrug resistance is a significant drawback in malaria treatment, and mutations in the active sites of the many critical antimalarial drug targets have remained challenging. Therefore, this has necessitated the global search for new drugs with new mechanisms of action. <jats:italic>Plasmodium falciparum<\/jats:italic> lactate dehydrogenase (<jats:italic>pf<\/jats:italic>LHD), a glycolytic enzyme, has emerged as a potential target for developing new drugs due to the parasite reliance on glycolysis for energy. Strong substrate\u2010binding is required in <jats:italic>pf<\/jats:italic>LDH enzymatic catalysis; however, there is a lack of information on small molecules\u2019 inhibitory mechanism bound to the substrate\u2010binding pocket. Therefore, this study investigated a potential allosteric inhibition of <jats:italic>pf<\/jats:italic>LDH by targeting the substrate\u2010binding site. The structural and functional behaviour of madecassic acid (MA), the most promising among the six triterpenes bound to <jats:italic>pf<\/jats:italic>LDH, were unravelled using molecular dynamic simulations at 300\u2005ns to gain insights into its mechanism of binding and inhibition and chloroquine as a standard drug. The docking studies identified that the substrate site has the preferred position for the compounds even in the absence of a co\u2010factor. The bound ligands showed comparably higher binding affinity at the substrate site than at the co\u2010factor site. Mechanistically, a characteristic loop implicated in the enzyme catalytic activity was identified at the substrate site. This loop accommodates key interacting residues (LYS174, MET175, LEU177 and LYS179) pivotal in the MA binding and inhibitory action. The MA\u2010bound <jats:italic>pf<\/jats:italic>LHD average RMSD (1.60\u2005\u00c5) relative to chloroquine\u2010bound <jats:italic>pf<\/jats:italic>LHD RMSD (2.00\u2005\u00c5) showed higher stability for the substrate pocket, explaining the higher binding affinity (\u221233.40\u2005kcal\/mol) observed in the energy calculations, indicating that MA exhibited profound inhibitory activity. The significant <jats:italic>pf<\/jats:italic>LDH loop conformational changes and the allostery substrate\u2010binding landscape suggested inhibiting the enzyme function, which provides an avenue for designing antimalarial compounds in the future studies of <jats:italic>pf<\/jats:italic>LDH protein as a target.<\/jats:p>","DOI":"10.1002\/cbdv.202100646","type":"journal-article","created":{"date-parts":[[2022,1,4]],"date-time":"2022-01-04T14:05:54Z","timestamp":1641305154000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["An Allosteric Inhibitory Potential of Triterpenes from <i>Combretum racemosum<\/i> on the Structural and Functional Dynamics of <i>Plasmodium falciparum<\/i> Lactate Dehydrogenase Binding Landscape"],"prefix":"10.1002","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3646-2488","authenticated-orcid":false,"given":"Wande M.","family":"Oluyemi","sequence":"first","affiliation":[{"name":"Laboratory for Natural Products and Biodiscovery Research Pharmaceutical Chemistry Department Faculty of Pharmacy University of Ibadan  Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1834-9548","authenticated-orcid":false,"given":"Babatunde B.","family":"Samuel","sequence":"additional","affiliation":[{"name":"Laboratory for Natural Products and Biodiscovery Research Pharmaceutical Chemistry Department Faculty of Pharmacy University of Ibadan  Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7645-5517","authenticated-orcid":false,"given":"Adeniyi T.","family":"Adewumi","sequence":"additional","affiliation":[{"name":"Molecular Bio-computation and Drug Design Laboratory School of Health Sciences University of KwaZulu-Natal  Westville Campus Durban 4001 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9392-3925","authenticated-orcid":false,"given":"Yemi A.","family":"Adekunle","sequence":"additional","affiliation":[{"name":"Laboratory for Natural Products and Biodiscovery Research Pharmaceutical Chemistry Department Faculty of Pharmacy University of Ibadan  Nigeria"},{"name":"Department of Pharmaceutical Chemistry Dora Akunyili College of Pharmacy Igbinedion University  Okada Benin City Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8711-7783","authenticated-orcid":false,"given":"Mahmoud E. 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