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

• DOI: 10.1007/s12013-025-01709-2
• Publication Date: 2025-03-21T23:09:55Z
• Authors: Ernest Oduro-Kwateng; Ibrahim Oluwatobi...; Musab Ali; Kabange Kasumbwe; Vuyisa Mzozoyana; Narasimham L. Par...; Mahmoud E. S. Sol...
• Keywords: Dihydroartemisinin; Artesunate; Artemether

Abstract Human malaria remains a global health challenge, with Plasmodium falciparum responsible for the most severe cases. Despite efforts, eradicating has proven difficult, mainly because of rise in drug resistance, particularly against artemisinin and its derivatives. One possible cause this resistance is activation unfolded protein response (UPR), which helps maintain cellular balance under stress. In P. , UPR operates through ubiquitin-proteasome system (UPS), involves proteins such as Dsk2, Rad23, Ddi1. Among these, DNA-damage-inducible 1 ( Pf Ddi1) plays crucial role DNA repair present throughout parasite life cycle, making it an attractive target. However, there limited research on Ddi1 therapeutic Recent vitro studies have indicated that (ART) dihydroartemisinin (DHA) inhibit activity. Building this, we investigated whether ART derivatives could serve inhibitors using computational modeling. Our study included clinically relevant artemether (ARM), arteether (AET), artemiside (AMD), artesunate (ATS). All these compounds showed strong binding to Ddi1, free energies ranging from −20.75 kcal/mol AET −34.24 ATS. ARM increased Ddi1’s structural rigidity hydrophobic stability, whereas AMD improved kinetic resulting least residue motion. Unlike AMD, other ligands destabilize structure. Importantly, three key regions—Loop (GLN 266 - ILE 269), Loop 2 (ILE 323 TYR 326), 3 (ALA 292 GLY 294)—were identified potential targets new antimalarial drugs This highlights inhibitors, paving way further experimental validation. Graphical