In silico identification of potential inhibitors for the universal stress G4LZI3 protein from Schistosoma mansoni using molecular docking and molecular dynamics simulation analyses

Abstract

Human schistosomiasis is a debilitating, neglected tropical disease affecting millions worldwide. Control efforts primarily rely on health education, improved sanitation, snail host management, and mass drug administration with Praziquantel (PZQ). PZQ has some limitations, such as its lower effectiveness against immature parasites and the potential for developing resistance. This requires the urgent need for new treatment approaches. The universal stress protein G4LZI3 helps the Schistosoma mansoni parasite survive when it is under stress from its host. Because of this, it emerges as a promising target for developing new drugs. Despite its biological relevance, G4LZI3 has not been previously investigated as a druggable target, highlighting a significant research gap in schistosomiasis drug discovery. To find potential inhibitors of G4LZI3, we conducted a virtual screening using the RASPD⁺ tool, which led us to select 7889 ligands from the CoCoNut database. These ligands were filtered based on physicochemical properties (Lipinski's Rule of Five, Veber's Rule, Egan's Filter, and the Ghose filter), pharmacokinetics, and Pan-Assay Interference Structures (PAINS) criteria, followed by molecular docking. Fifteen compounds demonstrated strong binding affinities, with binding energies ranging from −10.6 to −8.50 kcal/mol, exceeding that of PZQ (−8.4 kcal/mol). From these, six compounds were selected for further analysis, including molecular dynamics (MD) simulation, solvent-accessible surface area (SASA), and molecular mechanics generalized Born surface area (MM-GBSA) calculations. MD simulation of 200 ns revealed that CNP0475438, CNP0415153, and CNP0353858 achieved significant stability and favourable interactions with G4LZI3. These findings show these compounds as promising candidates for S. mansoni inhibition, pending experimental validation. The results identify novel scaffolds with vigorous predicted activity and provide a rational starting point for experimental optimization and development of new antiparasitic therapies that address praziquantel resistance and efficacy limitations in endemic regions.