Development and application of Fragment-based De novo inhibitors against Plasmodium falciparum GST

Abstract

Modulation of disease progression is frequently started by identifying biochemical pathway catalyzed by biomolecule that is prone to inhibition by small molecular weight ligands. Such ligands (leads) can be obtained from natural resources or synthetic libraries. However de novo design based on fragments assembly and optimization is showing increasing success. In this research, fragment-based approaches were used to design molecules that can fit glutathione (GSH) binding site of Plasmodium falciparum GST (PfGST). The involved approaches build molecules from fragments that are either isosteric to GSH sub-moieties (ligand-based) or successfully docked to GSH binding sub-pockets (structure-based). Selected fragments are joined to create ligands that were explored using molecular docking, Cartesian coordinate’s optimization, and simplified free energy determination as well as MD simulation and MMPBSA calculations. Compared to reference GST inhibitor of S-hexyl GSH, ligands with improved rigidity, synthetic accessibility and affinity to receptor were successfully designed.

Exploring the Infectious Drug Target Glutathione S-Transferase in Plasmodium falciparum with the Inhibitory Potential of Azadirachta indica Phytocompounds

“…The molecular interactions between proteins and drugs, for instance, or the spread of disease in a population, can both be studied with the help of in silico methods [33,34]. The malaria parasite, Plasmodium falciparum, requires the GST enzyme to function properly [35]. Some hypothesize that neem extracts are effective Advances in Public Health because they disrupt the parasite's cell membrane, slow its growth, and inhibit its metabolism.…”