In silico Design of Acteoside Analogues to Target Resistant Plasmodium and Enhance Antimalarial Efficacy

Abstract

The rise of multidrug-resistant Plasmodium strains calls for urgent attention. This computational study investigates the drug-likeness, pharmacokinetic properties, toxicity profiles, and molecular docking affinities of three acteoside derivatives, designated Dact, Pact, and Cact, relative to artemisinin and chloroquine. Dact, Pact, and Cact were drawn and optimized, and their toxicity, ADME properties, and molecular docking were evaluated using SwissADME, pkCSM, and the MM-GBSA method, respectively. Density Functional Theory (DFT) calculations were also performed. All compounds met Lipinski and Veber rules (bioavailability 0.55). Dact was most polar/ soluble; chloroquine was most lipophilic. All showed high GI absorption; only artemisinin and chloroquine crossed the BBB. Dact was non-mutagenic and non-hepatotoxic, unlike others (mutagenic) and chloroquine (hepatotoxic). Dact showed the strongest binding to both Plasmodium targets, outperforming references. DFT confirmed Dact's smallest energy gap, indicating high reactivity against CRT/MDR1. The superior binding and reactivity of Dact suggest its potential to inhibit resistance mechanisms (CRT/MDR1). Unlike chloroquine, Dact lacks hepatotoxicity and mutagenicity, improving safety. Its high polarity limits BBB penetration, reducing CNS side effects. These computational advantages warrant in vitro validation. These findings position Dact as a promising antimalarial candidate, with potential to overcome resistance, enhance efficacy, and improve safety.