Integrated Molecular Docking, DFT, ADME Profiling, and Cardiotoxicity Prediction of Artocarpin, Cycloartocarpin, Artocarpanone and Cyanomaclurin as Potential Antimalarial Agents

The escalating resistance of Plasmodium falciparum to existing antimalarial treatments necessitates the identification of novel medicines with enhanced efficacy and safety. This study utilized a comprehensive in silico approach to assess the potential of four flavonoids from Artocarpus heterophyllus î.e. artocarpin, cycloartocarpin, artocarpanone, and cyanomaclurin as inhibitors of P. falciparum dihydrofolate reductase–thymidylate synthase (PfDHFR-TS). Molecular docking demonstrated that artocarpin and cycloartocarpin displayed enhanced binding affinities and advantageous interaction patterns compared to chloroquine. Density functional theory and molecular electrostatic potential investigations corroborated their increased electronic reactivity and binding compatibility. ADME profiling demonstrated satisfactory drug-likeness properties; however, cardiotoxicity prediction revealed artocarpin and cycloartocarpin as non-hERG blockers, unlike chloroquine. Despite the anticipated mild toxicity hazards, the comprehensive computational data underscore artocarpin and cycloartocarpin as prospective lead scaffolds for subsequent optimization. These findings provide a compelling justification for the experimental validation and rational design of safer antimalarial medicines derived from A. heterophyllus.