Search for Lead Compounds and In Vitro Assay of Potential Inhibitors of Plasmodium falciparum Prolyl-tRNA Synthetase from Natural Compound Database

Malaria continues to be a serious problem in several countries, marked by an increase in the number of cases and a high morbidity rate. One of the commonly adopted strategies in drug discovery is by performing compound screening using computational tools, known as virtual screening. This technique allows one to screen multitudes of chemical compounds in silico, thus saving cost and time by reducing the amount of tested compound in vitro. Recently, P. falciparum prolyl-tRNA synthetase (PfPRS) is one of the top priority targets to be explored of potent inhibitors. This enzyme plays an important role in attaching L-proline into tRNA, which then will be incorporated into protein sequence. Its inhibition would halt the protein synthesis and kill the parasite.

Hierarchical virtual screening was performed against PfPRS enzyme using 2D followed by 3D similarity method implemented in Infinisee 3.2.0 and SeeSAR 12.1.0, respectively. 1-(pyridin-4-yl) pyrrolidin-2-one based analog, which was previously discovered as potent antimalarial agent, was used as template to screen potential hits from Molport Database of Purchasable Natural Product Compounds. Compounds with high similarity value were evaluated by molecular docking using SeeSAR 12.1.0 approach. The best scoring compounds were subjected into ADMET prediction, molecular dynamics simulation, and in vitro assay against P. falciparum.

Two compounds were obtained from virtual screening and molecular docking process, with predicted IC₅₀ value lies on micromolar and nanomolar range. These compounds also satisfy ADMET characteristics in general as well as showing stability during 100 ns molecular dynamics simulation. Bioassay study showed that both compounds yielded < 10 µg/mL inhibitory concentration.

This study has discovered two novel compounds using in silico approach, which can be further developed as potential antimalarial agents.