De novo design of inhibitors of histone deacetylase 8 for the treatment of schistosomiasis

Neglected tropical diseases (NTDs) are a group of infectious diseases that affect impoverished regions and remain under-researched due to their limited presence on the global health agenda. One such disease is schistosomiasis, caused by the parasite Schistosoma mansoni. To identify potential new treatments for schistosomiasis, we performed de novo design of small molecules targeting the epigenetic enzyme smHDAC8 using LigBuilder V3. We computationally predicted an allosteric cavity on the surface of smHDAC8 with the potential for binding drug-like molecules. Based on this finding, we generated nine smHDAC8-focused compound libraries, resulting in the design of 2,355 unique molecules, which are freely available at https://github.com/DIFACQUIM/De_novo_design_of_focused_smHDAC8_libraries.git. Following standardization, all compounds underwent virtual screening using molecular docking with two docking programs. We assessed ligand efficiency, synthetic accessibility, molecular similarity indices, and scaffold diversity. The top 40 compound candidates were selected based on docking scores, with 20 chosen specifically for their ligand efficiency. All compounds selected have a favorable synthetic accessibility score. These molecules represent promising candidates for further experimental validation in the search for novel schistosomiasis treatments.