During the intraerythrocytic stage, one of the primary actions of antimalarials is to disrupt the parasite's heme detoxification mechanism by preventing the crystallization of hematin. We examine the cooperative effects of artemisinin-based combination therapies (ACTs) on β-hematin inhibition, focusing on both the formation and growth of hematin crystals. We evaluate a two-drug combination, hematin-dihydroartemisinin adduct (H-DHA) with Lumenfantrine (LF), as well as two triple-drug combinations: H-DHA, LF, and Amodiaquine (AQ); and H-DHA, Piperaquine (PQ), with Mefloquine (MQ). By integrating pharmacokinetic parameters with molecular-level cooperativity data, we elucidate how combination therapies work on inhibition of hematin crystallization comparing with individual drug. Additionally, we assessed the impact of these drug combinations on the nucleation phase of hematin crystallization, which is critical during the ring stage of the parasite. This integrated approach provides new insights into the interactions among multiple antimalarial agents and their cumulative effect on β-hematin, potentially guiding the development of more effective therapeutic strategies against malaria.
