in depth in silico exploration of some natural indole alkaloids as potential plasmepsin ii inhibitors: admet calculations, molecular docking analysis, molecular dynamics simulation, and dft studies

Plasmepsin ii, an aspartic protease enzyme found in the malarial parasite plasmodium falciparum, plays a critical role in malaria pathogenesis. quinine, quinidine, cinchonine, and cinchonidine are four quinoline alkaloids derived from cinchona officinalis bark that have a human malaria cure rate exceeding 98%. in terms of intra-erythrocytic malarial parasites, quinine is schizonticidal and gametocytocidal for plasmodium vivax and plasmodium malaria, whereas it has no effect on p. falciparum gametocytes. therefore, this study investigates natural indole alkaloids as potential inhibitors of plasmepsin ii for treating p. falciparum malaria. the admet profiles of the selected indole alkaloids were calculated and the binding affinity of the ligand with plasmepsin ii was determined. the desmond program ran a molecular dynamic simulation (mds) at 100 ns to verify the stability and function of the complex in a physiological-chemical environment. ergocornine and native ligands were analyzed using density functional theory (dft) calculations to evaluate their electronic properties and reactivity. in admet screening, all the screened compounds displayed optimum admet profiles to be developed or treated as lead nuclei for further study. in computational screening, the native ligand displayed -7.5 kcal/mol of binding free energy, while most potent compound such as ergocornine exhibited -9.5 kcal/mol binding affinity. mds analysis showed that the complex displayed a very stable conformation and demonstrated compact ligand binding. dft studies indicated that ergocornine exhibited higher stability and lower reactivity compared to the native ligand, highlighting its potential for therapeutic applications. these natural alkaloids may possess potential anti-plasmepsin ii activity, which can be further investigated using numerous in vitro or in vivo models. we aim to report this finding in the future.