Screening of HDAC3/8 Small Molecule Inhibitors from Traditional Chinese Medicine Based on Molecular Docking / 中国实验方剂学杂志

ABSTRACT

Objective:To discover a small molecule active ingredient of traditional Chinese medicine (TCM) with the inhibitory activity of histone deacetylase (HDAC) 3/8. Method:The molecular docking technique was performed by AutoDock 4.2.6 software. Trichostatin A (TSA) was used as a reference to screen 19 small molecular components from TCM, and the default docking conformation number was set to obtain the docking binding energy, active site amino acid residues and hydrogen bonds, and the biological activity was verified. Result:The binding energies of 19 small molecule components from TCM to HDAC3 and HDAC8 were different. Among them, ursolic acid, fangchinoline and tetrandrine have low binding energies to HDAC3 and HDAC8, and their binding activities were strong. The optimal binding energy of fangchinoline and HDAC3 at the site 1 was the lowest (-26.71 kJ·mol-1), and that of HDAC8 at the site 9 was the lowest (-26.84 kJ·mol-1). The optimal binding energy of tetrandrine and HDAC3 at the site 13 was the lowest (-26.38 kJ·mol-1), and that of HDAC8 at the site 12 was the lowest (-25.41 kJ·mol-1). In addition, the binding energy of ursolic acid and HDAC3 at the site 16 was the lowest (-25.83 kJ·mol-1), and that of HDAC8 at the site 8 was the lowest (-35.62 kJ·mol-1). Three kinds of amino acids at the docking site of small molecules were rendered by PyMOL 2.3.1.When ursolic acid was combined with HDAC3/8, the active sites produced two hydrogen bonds, and the interaction was strong, and many amino acids were connected at the active site. The fangchinoline formed two hydrogen bonds with the active site of HDAC3 and one hydrogen bond with the active site of HDAC8, and hydrophobic binding with some active site amino acids. There was no hydrogen bond between tetrandrine and HDAC3/8, and all docking sites were docked by 4 active amino acids. Three small molecules (ursolic acid, fangchinoline and tetrandrine) with the best docking effect had the inhibitory activity against HDAC3/8 at the concentration of 500 μmol·L-1 and 100 μmol·L-1, and the inhibitory activity was still optimal among the 10 selected small molecules. Conclusion:Among the screened 19 small molecules, ursolic acid, tetrandrine and fangchinoline may be the new anti-inflammatory drugs of HDAC3/8 inhibitory target, which provides a reference for further exploration and discovery of new anti-inflammatory drugs.