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 physiologicalchemical 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 antiplasmepsin II activity, which can be further investigated using numerous in vitro
or in vivo models. We aim to report this finding in the future.