Unravelling selectivity discrepancies of protoporphyrin binding to glutathione transferase: A comparative analysis of molecular dynamic simulated versus implicit solvent-minimized protein models.

Schistosomiasis is a neglected tropical disease caused by parasitic trematodes, which are an ongoing global health and veterinary concern owing to their acquired drug resistance pressure to available treatment. There is a need for a new generation of effective anthelmintics for preventive and therapeutic purposes. Natural products, such as porphyrins, have been reported to inhibit the main detoxification enzymes in these parasites, called glutathione transferases, which help them evade immune response and drug therapy, thus making them good drug targets. Computational modelling was used to screen potential inhibitors out of 461 protoporphyrin IX-like compounds, including a potent known inhibitor called bromosulfophthalein. However, unlike traditional docking, where the stable energy-minimized structure is used, a short molecular dynamic simulation step was added to yield the most averaged protein structure conformation as the starting point of high throughput virtual screening. Here, it was shown that the starting point is crucial as the results suggested different lead compounds; for the 26-kDa japonicum GST, the top-scoring compounds were CID: 122690402 for the minimized structure and CID: 137797052 for the MD-simulated structure. Similarly, for the 28-kDa haematobium GST, the lead compounds were CID: 70415734 and CID: 69301914, respectively. These results highlight the importance of incorporating protein dynamics into structure-based drug design and provide valuable insights into the development of porphyrin-based therapeutics against schistosomiasis and other helminthic infections.