In-silico Exploration and Structure-Based Design of Praziquantel Derivatives as Potential Inhibitors of Schistosoma mansoni Glutathione S-transferase (SmGST)

Schistosomiasis is a chronic parasitic disease with significant public health challenges due to the limited number of treatment options and increasing levels of drug resistance against the only available drug, Praziquantel (PZQ). Consequently, there has been ongoing research in discovering new and more effective drugs for treating schistosomiasis. In this regards, structure-based drug design was employed to generate novel derivatives of PZQ with enhanced binding affinities. Molecular-docking simulations of twenty-four derivatives was performed, with the goal of identifying a prominent lead for further design. Among the screened derivatives, compound 23 showed the most favorable binding energies (Moldock score of -101.846 kcal mol−1) making it the preferred lead candidate. Five novel `compounds were designed, each demonstrating enhanced binding energies (ranging from -108.645 to -112.237 kcal mol−1) compared to the standard drug with a Moldock score of -90.663 kcal mol−1. Notably, 23d demonstrated the highest binding energies among the designed entities (-112.237 kcal mol−1). The identified compounds displayed potent inhibition of Schistosoma mansoni Glutathione S-transferase (SmGST) and met the drug-likeness criteria of the Lipinski, Ghose, Verber, and Egan. Additionally, a blood-brain barrier (BBB) value > -1 and a central nervous system (CNS) value > -3, signifying their capability to efficiently traverse the BBB and access the CNS. Furthermore, they were found to be non-AMES toxic, ensuring their safety in this regard. Molecular dynamic simulations and density function theory confirmed the ligands' chemical reactivity and ligand-complex stability under biological conditions. This makes them promising candidates for the development of drugs for treating Schistosomiasis.