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

Abstract

Introduction: 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. Method: 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. Results: 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. Discussion: 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. Conclusion: These findings position Dact as a promising antimalarial candidate, with potential to overcome resistance, enhance efficacy, and improve safety.