In this work, cytidine and fifteen of its derivatives have been examined to detect their Methyltransferase (MTF) enzyme inhibitory activity. 3D models of the ligands and MTF were extracted from PubChem and Protein Data Bank (PDB), respectively. All ligand structures were first optimized to obtain their minimum energy structures. Molecular features were obtained for the optimized structures. The molecular docking process was performed for all of the ligands versus MTF enzyme to obtain the interacting ligand-receptor complexes. The results indicated that, the derivatives of cytidine revealed better enzyme inhibitory activity compared with that of the original structures. Moreover, chemical modifications showed different impacts on the molecular features and enzyme activities. Therefore, it is important to choose the type of modifications to the desired chemical structure. Among the investigated derivatives, D4: Galocitabine showed the best properties to be proposed as the best inhibitors, and it is a great candidate for further investigations.