Molecular docking, density functional theory, and molecular dynamics study of pipecolisporin derivatives: Unveiling the antimalarial potential of novel cyclic peptides

Malaria remains a persistent global health issue, with escalating resistance to existing antimalarial treatments driving the urgent need for novel therapeutic agents. This study aimed to evaluate the in silico antimalarial potential of pipecolisporin analogs by investigating their binding affinity to key Plasmodium proteins and assessing their pharmacokinetic and toxicity profiles. We employed molecular docking and molecular dynamics (MD) simulations to investigate the interactions between pipecolisporin analogs and three key Plasmodium proteins: dihydrofolate reductase (2BL9), plasmepsin V (4ZL4), and lactate dehydrogenase (1CET). The pharmacokinetic (ADME) properties and toxicity of the analogs were predicted using cheminformatics tools to assess their potential bioavailability and safety. Among the tested compounds, analog-3 demonstrated the highest binding affinity with 2BL9 (−13.02 kcal/mol) and 4ZL4 (−8.07 kcal/mol). MD simulations confirmed the stability of the analog-3-protein complexes, reinforcing its potential as an effective enzyme inhibitor. ADME predictions showed that all analogs had low gastrointestinal absorption and poor ability to cross the blood-brain barrier. Toxicity assessments indicated the presence of neurotoxic and respiratory risks across all analogs. Despite pharmacokinetic limitations and toxicity concerns, pipecolisporin analogs, particularly analog-3, exhibit strong inhibitory potential against key Plasmodium proteins. With further structural optimization to improve bioavailability and reduce toxicity, these compounds hold promise as novel antimalarial agents.