Preliminary In Silico Identification of a Brain-Penetrant HDAC6 Inhibitor (ZINC_SYN_0021), Targeting Tau Acetylation at KXGS Motifs

Abstract

The Cytoplasmic deacetylase HDAC6 is responsible for removing tau acetylation at the KXGS motifs (K259, K290, K321, K353). The tau acetylation is a protective post-translational modification that prevents pathological phosphorylation and thus reduces tau aggregation. Inhibiting HDAC6 pharmacologically averts tau pathology in animal models, making HDAC6 an attractive target for tauopathy. We report a preliminary in silico framework to identify potential drug candidates that target  HDAC6, a key enzyme involved in tau protein dysfunction in Alzheimer's disease. We used the 3D crystal structures of the HDAC6 catalytic domain and tau protein as targets. A library of brain-permeable, zinc-binding compounds was screened through step-by-step virtual docking, which was validated using twelve clinically known HDAC inhibitor drugs. The top-ranked compound was further evaluated through molecular dynamics simulations to assess its stability when bound to HDAC6 and three different modified forms of tau protein. Finally, binding energy calculations (MM-GBSA) and drug-safety profiling (ADMET) were performed to confirm the suitability of the lead compound as a potential therapeutic candidate. Among all tested compounds, ZINC_SYN_0021 (SMILES: O=C(CCCC/C=C/c1ccc(OC)c(OC)c1)NO), a small hydroxamic acid molecule, emerged as the top candidate. It showed strong binding to HDAC6, comparable to two clinically approved HDAC inhibitor drugs (vorinostat and ACY-1215). Its binding energy was approximately −45 kcal/mol, indicating a stable and favorable interaction. Importantly, the compound was predicted to cross the blood-brain barrier, making it suitable for brain-targeted therapy. It also showed no major safety concerns related to the heart or liver. Molecular dynamics simulations revealed that acetylated tau adopted a more compact and stable conformation compared to phosphorylated tau, suggesting lower aggregation tendency- a finding that supports previously reported biological evidence. We present this computational framework along with its current findings and acknowledged limitations. The values reported here are preliminary outputs of an ongoing pipeline and must be experimentally validated before any therapeutic conclusions can be drawn.