Integrated virtual screening, ADMET profiling, and molecular dynamics simulations of novel natural HDAC6 inhibitors with the potential to ameliorate skeletal muscle degeneration

Histone deacetylase 6 (HDAC6) helps maintain muscle health and regulates protein balance. In atrophic muscle, increased HDAC6 activity destabilizes microtubules and intensifies protein degradation. Therefore, selective HDAC6 inhibition is a promising approach to preserving muscle health. In this study, we conducted a comprehensive computational analysis, including virtual screening of 449,058 natural compounds from the SuperNatural 3.0 database, to identify novel natural HDAC6 inhibitors. The top candidates were filtered for drug-likeness and ADMET properties, then subjected to molecular docking and molecular dynamics simulations (MDS) to evaluate binding stability and energy profiles. The 20 best-scoring compounds (range of LibDock score: 120.54 to 167.81) were visually analyzed for their docking poses, and top-ranked compounds, SN0000021 and SN0000043, were selected for evaluation. Two natural compounds, SN0000021 and SN0000043, consistently showed strong predicted binding, favorable pharmacokinetic features, and stable interaction with the HDAC6 catalytic pocket throughout a 200-ns MDS. SN0000021 has moderate solubility, high Caco-2 permeability, and ~ 93% intestinal absorption, while SN0000043 shows slightly higher solubility, moderate permeability, and ~ 75% absorption. Both are AMES non-toxic and synthetically accessible. Free-energy calculations further confirmed their binding potential. These results indicate that SN0000021 and SN0000043 are plausible natural scaffolds for the development of selective HDAC6 inhibitors. Experimental validation in HDAC6 enzyme assays and SM models is required to confirm their anti-atrophic effects.