Histone deacetylases 2 (HDAC2) proteins belongs to Class I histone deacetylase (HDAC) family and an important target for the treatment of different types of cancer. Of the various HDAC2 inhibitors, our earlier investigations proved that presence of histidine moiety yielded better clinical results. The search of histidine containing compounds is done extensively which yielded a total of 1284 hit compounds. The chosen compounds were subjected to molecular docking in the active site of HDAC2 (PDB: 3MAX) and screening done based on Lipinski rule of 5, resulted in twenty hit compounds as novel potential HDAC2 inhibitors. The careful analysis of the investigation gave the compound ZINC13282319-(2S)-2-(3-aminopropanamido)-3-(3H-imidazol-4-yl)propanoic acid as the most promising compound based on the docking score and hydrogen bond interaction. The best possible interactions of the lead compounds are simulated for stability using molecular dynamics. The results of this investigation provide valuable information on the design of highly selective histidine derivatives.