Histone deacetylases (HDACs) belong to a superfamily of enzymes responsible for deacetylating the Nterminal tails of histones. Overproduction of HDACs has a significant role in tumorigenesis. Accordingly, inhibition of HDACs has been widely applied for cancer therapy. It is encouraging that some natural products showed promising potency and selectivity against HDACs. In order to uncover their keys of good performance, the binding patterns of several natural HDAC1 inhibitors in the active site of HDAC1 were navigated by homology modeling, docking and molecular dynamic simulations. Evaluation of the binding poses allowed us to recognize the roles of different residues around the active site, and to understand the core features in the structure of the inhibitor molecule. Hydrophobic and H-bond interactions formed between the ligand and residues were discovered to make significant contributions to the ligand-receptor binding. Finally, the structural requirement of inhibitors for binding to HDAC1 was well proposed. Our results are beneficial to the design of potent HDAC1 inhibitors.