Quantum-Mechanically Refined, Dynamics-Coupled, and AI-Augmented Elucidation of Epigenetic Inhibition: An In Silico...

The increasing burden of schistosomiasis, compounded by the restriction imposed by monotherapeutic regimens, highlights the pressing need for new molecules that target specific molecular pathways. Schistosoma mansoni histone deacetylase 8 (SmHDAC8), a zinc-dependent epigenetic regulator, has emerged as a nonredundant and druggable enzyme, critical for parasite survival, fertility, and chromatin homeostasis. In this study, we outline multiple-mode computational analysis involving structure-based virtual screening against a chemically diverse ligand library, frontier molecular orbital analysis through DFT, large-scale molecular dynamics (MD) simulations (500 ns), and molecular mechanics/gas-phase/Generalized Born (MM/GBSA) energy component analysis, complemented with machine learning-guided pIC₅₀ model building and prediction. Our screening cascade comprising docking, MM, and MD identified the lead candidate, 24374890, with the best docking score (-9.5 kcal/mol) and desirable electronic configuration (HOMO-LUMO gap: 4.143 eV) for its optimal reactivity-stability balance. MD simulations confirmed its stability in the short term, as well as its conformational preservation in the SmHDAC8 catalytic pocket, as evidenced through low RMSD values, stable free energy basins, and sustained intermolecular interactions. Hydrogen bond analysis proved that compounds 24374890 and 24280440 kept 1-4 stable hydrogen bonds for the entire 500 ns simulation, supporting their strong and stable binding in SmHDAC8's active site. Thermodynamic calculations through MM/GBSA indicated 24374890 has the best energetics for binding (ΔG_total = -65.11 kcal/mol), comprising largely van der Waals and nonpolar solvation energies. Finally, the pIC₅₀ value for 24374890 was predicted, through supervised machine learning, as 8.1, better than the reference molecule. These convergent findings from quantum mechanical, molecular mechanical, and AI-based computations validate 24374890 as an SmHDAC8 inhibitor that is structurally and dynamically sound. These calculations need to be supported with in vitro enzyme inhibition experiments against recombinant SmHDAC8 and cytotoxicity profiling in schistosome cultures. Moreover, X-ray crystallography or cryo-EM analysis of the SmHDAC8-24374890 complex would reveal detailed binding conformations.