"Novel Inhibitors of enzyme HGXPRT Targeting Malaria Parasite Plasmodium falciparum through biochemical and biophysical methods: A Step Toward Healthier Communities"

Malaria is an infectious and vector-borne parasitic disease spread to humans by mosquitoes. According to 2024 report of WHO, malaria cases climbed from 2023 when compared to the ratio of 2022 with an estimation of 11 million, 263 million malaria cases recorded in 2023 worldwide and the mortality rate also exceeded by three times. In endemic countries, 250 million malaria cases reported in 2022. As study demonstrate that Pakistan accounts for the largest cases reported owing to climatic change in 2022 with 2.6 million cases and majority of malaria cases were reported from Sindh and Balochistan province of Pakistan. Malarial parasite depends on the salvage pathways for its purine nucleotide synthesis, as it lacks the denovo pathway. This research project was designed to disrupt the Salvage pathway as a result it will lead to parasite death. The therapeutic target HGXPRT plasmid was transformed in prokaryotic system, additionally HGXPRT enzyme was expressed, and purified via affinity chromatography and proceeded for functional activity. For compounds screening lab standard inhibitor of this target was optimized and approximately 500 molecules including (Drugs, Synthetic compounds, and commercially synthesized compounds) were screened against the HGXPRT enzyme, as a result 42 compounds were found to be active against the enzyme HGXPRT. Along with this, identified inhibitors were validated through STD-NMR experiments to check protein ligand interaction. At, last these active compounds were checked for cytotoxicity by MTT assay on BJ cell line. This study thereby identifies leads against HG(X)PRT enzyme which can be studied further as potential antimalarial agents.

Keywords:  therapeutic targets, salvage pathway, STD-NMR, HGXPRT,  Drug discovery.