Schistosomiasis remains a major neglected tropical disease, with praziquantel as the only widely used therapy and limited efficacy against immature parasite stages. Histone deacetylase 8 from Schistosoma mansoni (smHDAC8) is an attractive epigenetic target expressed throughout the parasite life cycle, but achieving isoform selectivity remains a significant hurdle due to the high conservation of the catalytic pocket. Targeting allosteric sites offers an opportunity to modulate enzyme function while potentially improving selectivity. Here, we report a fragment-based de novo design campaign aimed at targeting a previously described allosteric cavity of smHDAC8, to circumvent these selectivity issues. Nine focused libraries comprising 2,355 unique small molecules were generated from synthetic and natural productderived fragments, including the specialized CRAFT library alongside natural products libraries. Consensus virtual screening prioritized 40 candidates, including 20 selected for high ligand efficiency, that outperformed the reference allosteric ligand NF2889. Subsequent molecular dynamics simulations identified four ligands that stably bind the allosteric pocket and favorably influence long-range dynamic communication with the catalytic site. These prioritized compounds represent a novel chemical space for the development of highly selective, non-hydroxamate smHDAC8 modulators to support further medicinal chemistry optimization and experimental validation. All structures and associated data are publicly available in https://github.com/DIFACQUIM/De_novo_design_of_focused_smHDAC8_libraries.git.
DO - 10.26434/chemrxiv-2025-d2c8t/v2 N2 -Schistosomiasis remains a major neglected tropical disease, with praziquantel as the only widely used therapy and limited efficacy against immature parasite stages. Histone deacetylase 8 from Schistosoma mansoni (smHDAC8) is an attractive epigenetic target expressed throughout the parasite life cycle, but achieving isoform selectivity remains a significant hurdle due to the high conservation of the catalytic pocket. Targeting allosteric sites offers an opportunity to modulate enzyme function while potentially improving selectivity. Here, we report a fragment-based de novo design campaign aimed at targeting a previously described allosteric cavity of smHDAC8, to circumvent these selectivity issues. Nine focused libraries comprising 2,355 unique small molecules were generated from synthetic and natural productderived fragments, including the specialized CRAFT library alongside natural products libraries. Consensus virtual screening prioritized 40 candidates, including 20 selected for high ligand efficiency, that outperformed the reference allosteric ligand NF2889. Subsequent molecular dynamics simulations identified four ligands that stably bind the allosteric pocket and favorably influence long-range dynamic communication with the catalytic site. These prioritized compounds represent a novel chemical space for the development of highly selective, non-hydroxamate smHDAC8 modulators to support further medicinal chemistry optimization and experimental validation. All structures and associated data are publicly available in https://github.com/DIFACQUIM/De_novo_design_of_focused_smHDAC8_libraries.git.
PB - American Chemical Society (ACS) TI - Structure-Based De Novo Design of Novel Allosteric smHDAC8 Modulators: A Fragment-Based Strategy to Combat Schistosomiasis UR - https://chemrxiv.org/doi/pdf/10.26434/chemrxiv-2025-d2c8t/v2 ER -