Investigation of the effects of some thiosemicarbazone and coumarin compounds on 6PGD and G6PD enzyme activities in vitro and in silico

This study aimed to look for compounds that could inhibit two enzymes involved in the pentose phosphate pathway (PPP), 6-phosphogluconate dehydrogenase (6PGD) and glucose-6-phosphate dehydrogenase (G6PD). PPP plays a crucial role in cancer cells and provides them with NADPH and ribose-5-phosphate to aid growth and survival. G6PD and 6PGD are important enzymes in the PPP, and their overexpression has been associated with multiple cancers. In this study, we examined how two groups of compounds modified in the laboratory affect the G6PD and 6PGD enzymes. The first group contains 6 coumarin derivative compounds, and the second group contains 11 thiosemicarbazone derivative compounds. The study investigated how the two groups affect these enzymes. By blocking these enzymes, it is possible to target cancer cells without harming normal cells. We investigated how these two groups interact with the G6PD and 6PGD enzymes by examining their enzyme activities. Some compounds inhibited both enzymes perfectly. Of the first group of compounds, C-3 is the most potent inhibitor. C-3 has an IC50 value of approximately 16.9 µM against the G6PD enzyme, C-2 18.733 µM, and C-4 20.386 µM. The weakest compound is C-6 77.016 µM. C-4 has an IC50 value of approximately 21.6 µM on the 6PGD enzyme, C-2, and C-3 25,672. The weakest compound is C-6 77.016 µM. In the second group, the most potent inhibitor is Y-5. The most potent inhibitor is Y-5 (G6PD) with an IC50 value of 4.303 µM, whose effects are weaker at lower concentrations. The weakest compound is Y-0 177.730 µM. The IC50 value of Y-5 (6PGD) is approximately 3.128 µM. The weakest compound is Y-10 133.297 µM. According to the study, these compounds showed inhibitory activity against both 6PGD and G6PD. The implication here is that these compounds could become valuable anticancer drugs if they target the PPP. Compound C-3 offers the most potent inhibitory activity against G6PD at an IC50 of 16.9 µM. Molecular docking analyses revealed that C-3 forms strong hydrogen bonding and π-π stacking with key residues TYR C:401, ARG C:370, and TRP C:509 in the active site. Likewise, thiosemicarbazone compound Y-5 was the most potent 6PGD inhibitor with an IC50 of 3.128 µM interacting with key residues MET B:14, ASN B:103, and VAL B:75 through stable H-bonds and hydrophobic interactions. Molecular dynamics studies have revealed the conformational adaptability of both enzymes and ligands to improve binding specificity under physiological conditions. The adaptability contributed to stable binding energies with C-3 and Y-5 optimally oriented and interacting to inhibit enzyme action. The results highlight the possible selective PPP inhibition ability of these compounds, which may lead to targeted anticancer therapy.