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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.

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