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Despite global efforts, eradicating malaria has proven difficult, mainly because of the rise in drug resistance, particularly against artemisinin and its derivatives. One possible cause of this resistance is the activation of the unfolded protein response (UPR), which helps maintain cellular balance under stress. In <jats:italic>P. falciparum<\/jats:italic>, the UPR operates through the ubiquitin-proteasome system (UPS), which involves proteins such as Dsk2, Rad23, and Ddi1. Among these, <jats:italic>Plasmodium falciparum<\/jats:italic> DNA-damage-inducible protein 1 (<jats:italic>Pf<\/jats:italic>Ddi1) plays a crucial role in DNA repair and is present throughout the parasite life cycle, making it an attractive drug target. However, there is limited research on <jats:italic>Pf<\/jats:italic>Ddi1 as a therapeutic target. Recent in vitro studies have indicated that artemisinin (ART) and dihydroartemisinin (DHA) inhibit <jats:italic>Pf<\/jats:italic>Ddi1 activity. Building on this, we investigated whether ART and its derivatives could serve as inhibitors of <jats:italic>Pf<\/jats:italic>Ddi1 using computational modeling. Our study included clinically relevant ART derivatives such as artemether (ARM), arteether (AET), artemiside (AMD), and artesunate (ATS). All these compounds showed strong binding to <jats:italic>Pf<\/jats:italic>Ddi1, with free binding energies ranging from \u221220.75\u2009kcal\/mol for AET to \u221234.24\u2009kcal\/mol for ATS. ARM increased <jats:italic>Pf<\/jats:italic>Ddi1\u2019s structural rigidity and hydrophobic stability, whereas AMD improved its kinetic stability, resulting in the least residue motion. Unlike AET and AMD, the other ligands destabilize the <jats:italic>Pf<\/jats:italic>Ddi1 structure. Importantly, three key binding regions\u2014Loop 1 (GLN 266 - ILE 269), Loop 2 (ILE 323 - TYR 326), and Loop 3 (ALA 292 - GLY 294)\u2014were identified as potential targets for new antimalarial drugs against <jats:italic>Pf<\/jats:italic>Ddi1. This study highlights the potential of ART derivatives as <jats:italic>Pf<\/jats:italic>Ddi1 inhibitors, paving the way for further experimental validation.<\/jats:p>\n          <jats:p>\n            <jats:bold>Graphical Abstract<\/jats:bold>\n          <\/jats:p>","DOI":"10.1007\/s12013-025-01709-2","type":"journal-article","created":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T19:09:55Z","timestamp":1742584195000},"page":"3277-3297","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Computational Analysis of Plasmodium falciparum DNA Damage Inducible Protein 1 (PfDdi1): Insights into Binding of Artemisinin and its Derivatives and Implications for Antimalarial Drug Design"],"prefix":"10.1007","volume":"83","author":[{"given":"Ernest","family":"Oduro-Kwateng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim Oluwatobi","family":"Kehinde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Musab","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kabange","family":"Kasumbwe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vuyisa","family":"Mzozoyana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narasimham L.","family":"Parinandi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud E. 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