In Silico Discovery and Screening of Small Molecule Inhibitors Targeting Glyceraldehyde-3-Phosphate Dehydrogenase ~ Triosephosphate Isomerase Protein Complex Towards New Anti-Schistosomal Drug Development

Abstract Schistosomiasis is a parasitic infection with significant health risks in developing countries due to the parasite’s immune system evasion and limited current treatments. Targeting metabolic enzymes essential for parasite survival offers a promising therapeutic approach. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Triosephosphate isomerase (TPI) represent the critical nature of such interactions as crucial enzymes in the glycolytic pathway. Inhibiting the interaction between GAPDH and TPI affects the interaction interface, although GAPDH is a particularly promising target. This is due to its roles in glycolysis, immune regulation, and host-parasite interactions. Despite prior studies focusing on GAPDH inhibition, few have specifically addressed the disruption of GAPDH ~ TPI interface in Schistosoma mansoni , impairing essential metabolic functions. The objective is to identify and characterize novel GAPDH inhibitors that block its enzymatic activity and protein-protein interaction. In this study, small molecule inhibitors of GAPDH were identified using an in-silico approach from a total of 26,784 compounds curated from the ChEMBL-NTD database using the RASPD + tool, thus yielding 7,042 potential inhibitors of GAPDH with minimum binding energies between − 5.43 kcal/mol and − 11.51 kcal/mol. Further filtering of these compounds using a -9 kcal/mol cut-off yielded 614 compounds with strong inhibitory potential. Physicochemical, pharmacokinetic, and medicinal chemistry properties filtering yielded 46 compounds subjected to docking using Praziquantel as a reference. Eight compounds with minimum binding energies from − 11.2 to − 9.2 kcal/mol, lower than Praziquantel’s 7.7 kcal/mol, were chosen and subjected to MD simulation and MM-GBSA analyses. This led to identifying three lead compounds (CID:44525857, CID:44534414, and CID:5051873) with stable binding, favourable interaction energies, and the potential to inhibit GAPDH functionality. These findings support their development as novel dual-action inhibitors targeting glycolytic enzymes in S. mansoni , with potential therapeutic value pending in vitro and in vivo validation.