Network pharmacology, molecular docking and molecular dynamics simulation suggest CE-326597 as an antimalarial...

Malaria remains a major health challenge, intensified by the spread of drug-resistant strains. To address this, we explored natural products and derivatives for antimalarial potential using in silico approaches. Through a similarity-based optimization strategy, molecular docking (Vina) and deep learning-based screening (Gnina) identified CE-326597 as a strong binder of Plasmodium falciparum enoyl-ACP reductase. Molecular dynamics simulations with a self-assembly setup showed spontaneous binding, with the ligand approaching the target from bulk solvent within 15 ns and maintaining stable interactions throughout 200 ns. Network pharmacology revealed that CE-326597 disrupts key parasite pathways (SRC, EGFR, ESR1) and modulates host receptors (HTR1A, HTR7, DRD4) linked to immune regulation. With a favorable safety profile from Phase 1 clinical trials for obesity, CE-326597 emerges as a promising repurposing candidate for malaria. Further in vitro and in vivo studies are warranted to confirm its therapeutic potential.

The online version contains supplementary material available at 10.1007/s40203-025-00508-0.