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Describing the ligandin properties of Plasmodium falciparum and vivax glutathione transferase towards bromosulfophthalein from empirical and computational modelling viewpoints.
Journal of Biomolecular Structure & Dynamics 2024 March 21
Research has spotlighted glutathione transferase (GST) as a promising target for antimalarial drug development due to its pivotal role in cellular processes, including metabolizing toxins and managing oxidative stress. This interest arises from GST's potential to combat multidrug resistance in existing antimalarial drugs. Plasmodium falciparum GST ( Pf GST) and Plasmodium vivax GST ( Pv GST) are key targets; inhibiting them not only disrupt detoxification but also reduce their antioxidant capacity, a critical feature for potent antimalarials. Bromosulfophthalein (BSP), a clinical liver function dye, emerged as a potent cytosolic GST inhibitor. This study explored BSP's inhibitory properties on Pf GST and Pv GST, showcasing its binding capabilities through empirical and computational analyses. The study revealed BSP's ability to significantly inhibit GST activity, altering the proteins' structures and stability. Specifically, BSP binding induced spectral changes and impacted the proteins' thermal stability, reducing their melting temperatures. Computational simulations highlighted BSP's strong binding to Pf GST and Pv GST at their dimer interface, stabilized by various interactions, including hydrogen bonds and van der Waals forces. Notably, BSP's binding altered the proteins' compactness and conformational dynamics, suggesting a potential non-competitive, allosteric inhibition mechanism. This study provided novel insights into BSP's candidacy as an antimalarial drug by targeting Pf GST and Pv GST. Its ability to disrupt crucial functions of these enzymes' positions BSP as a promising candidate for further drug development in combating malariaCommunicated by Ramaswamy H. Sarma.
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