Quantum mechanical (QM) calculations, molecular docking, and molecular dynamics (MD) simulations were performed to elucidate the influence of structural modifications on the binding affinity of newly designed monoamine oxidase B (MAO-B) inhibitors. In this line, after the optimizations of the structures of 70 new ligands and 15 reference compounds (existed drugs and hormones) using QM calculations, their interactions were analyzed by docking calculations to select the final 5 most appropriate ligands. These ligands were investigated by 300 ns MD simulations and the resulted trajectories were investigated using primary, structural (RMSD, RMSF, Rg, SASA, mindist, PCA), and interaction (hydrogen bonding and M-PBSA) analyzes. The results were promising, since all systems showed proper stability of the whole systems and significant interactions between the ligand and protein. To identify the most promising inhibitor candidates, in addition to comparing systems by considering equal contributions for each analysis, a weighted multi-parameter scoring framework was developed by integrating the results of twelve computational analyses, with each parameter assigned an appropriate weighting according to its relative importance. Noticeably, both scoring systems presented the similar ligand as the best inhibitor: 3OAc. In fact, meta position of the substituent and more electronegative substituent are the important factors which affect the interaction between the ligand and protein to be a more useful inhibitor.