A promising strategy to disrupt Plasmodium falciparum metabolic resilience by targeting G6PD: Virtual screening for potential inhibitors against malaria.

Malaria is a protozoan disease caused by the Plasmodium species. It is one of the top reasons for mortality globally, with 241 million cases and more than 6,27,000 deaths reported in 2020. The Pentose Phosphate Pathway (PPP) in Plasmodium falciparum plays a vital role in cellular metabolism, serving two main functions: generating ribose-5-phosphate for nucleotide biosynthesis and producing NADPH for reductive biosynthesis and oxidative stress regulation. The oxidative phase of the PPP is initiated by the allosteric enzyme glucose 6-phosphate dehydrogenase (G6PD), which catalyzes the conversion of glucose 6-phosphate into 6-phosphogluconolactone, leading to the production of NADPH. This NADPH is essential for maintaining redox balance and supporting biosynthetic processes in the parasite. Also, considering the importance of this enzyme, G6PD was chosen as the target for the current study. In identifying effective inhibitors against G6PD, structural similarity-based virtual screening, DFT, MMGBSA, ADME, and Toxicity prediction were employed. Based on previously reported compounds ML276 and ML304 as references, a shape-based screening approach was used to identify the best hit. The compounds with a sim score of 0.141 to 1.942 were chosen for further screening. Finally, four compounds, namely ZINC58252420, ZINC86331320, ZINC2046313, and ZINC521399619, were selected based on the scoring functions and their interactions. The ΔG binding values and docking scores showed a good relationship, indicating all four compounds could be specific inhibitors. These results provide further evidence that the compounds can act as effective inhibitors.