{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T14:01:19Z","timestamp":1777903279758,"version":"3.51.4"},"reference-count":61,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"vor","delay-in-days":355,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100014786","name":"Northern Border University","doi-asserted-by":"publisher","award":["NBU-CRP-2025-2043"],"award-info":[{"award-number":["NBU-CRP-2025-2043"]}],"id":[{"id":"10.13039\/501100014786","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Tropical Medicine"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p>\n                    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.\n                    <jats:italic>Schistosoma mansoni<\/jats:italic>\n                    histone deacetylase 8 (SmHDAC8), a zinc\u2010dependent epigenetic regulator, has emerged as a nonredundant and druggable enzyme, critical for parasite survival, fertility, and chromatin homeostasis. In this study, we outline multiple\u2010mode computational analysis involving structure\u2010based virtual screening against a chemically diverse ligand library, frontier molecular orbital analysis through DFT, large\u2010scale molecular dynamics (MD) simulations (500\u2009ns), and molecular mechanics\/gas\u2010phase\/Generalized Born (MM\/GBSA) energy component analysis, complemented with machine learning\u2013guided pIC\n                    <jats:sub>50<\/jats:sub>\n                    model building and prediction. Our screening cascade comprising docking, MM, and MD identified the lead candidate,\n                    <jats:bold>24374890<\/jats:bold>\n                    , with the best docking score (\u22129.5\u2009kcal\/mol) and desirable electronic configuration (HOMO\u2013LUMO gap: 4.143\u2009eV) for its optimal reactivity\u2013stability 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\u20134 stable hydrogen bonds for the entire 500\u2009ns simulation, supporting their strong and stable binding in SmHDAC8\u2019s active site. Thermodynamic calculations through MM\/GBSA indicated\n                    <jats:bold>24374890<\/jats:bold>\n                    has the best energetics for binding (\u0394G_total\u2009=\u2009\u221265.11\u2009kcal\/mol), comprising largely van der Waals and nonpolar solvation energies. Finally, the pIC\n                    <jats:sub>50<\/jats:sub>\n                    value for\n                    <jats:bold>24374890<\/jats:bold>\n                    was predicted, through supervised machine learning, as 8.1, better than the reference molecule. These convergent findings from quantum mechanical, molecular mechanical, and AI\u2010based computations validate\n                    <jats:bold>24374890<\/jats:bold>\n                    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\u2010ray crystallography or cryo\u2010EM analysis of the SmHDAC8\u2013\n                    <jats:bold>24374890<\/jats:bold>\n                    complex would reveal detailed binding conformations.\n                  <\/jats:p>","DOI":"10.1155\/jotm\/1172449","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T17:20:16Z","timestamp":1766424016000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Quantum\u2010Mechanically Refined, Dynamics\u2010Coupled, and AI\u2010Augmented Elucidation of Epigenetic Inhibition: An In Silico Paradigm Targeting HDAC8 of\n                    <i>Schistosoma 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