Introduction::The disability and mortality related to Parkinson's disease (PD), a
neurodegenerative disease, are increasing globally at a faster rate than other neurological disorders.
With no permanent cure for PD, there is an urgent need to develop novel and effective
anti-PD drugs.
Methods::Targeting monoamine oxidases (MAO), which catalyze the breakdown of
neurotransmitters, is one way to treat neurodegenerative diseases. In this context, an initial molecular
docking of twenty designed sulfonyl derivatives of benzimidazole against monoamine
oxidase B (MAO-B) associated with PD was conducted using AutoDock Vina.
Results::The results were compared with those of the conventional inhibitors, selegiline and
rasagiline. Based on the docking score, the in-silico pharmacokinetic properties (ADME),
drug-likeness, and toxicity profiles of the newly synthesized molecules were examined using
SwissADME, PreADMET, ProTox-3.0, vNN, and ADMETlab web tools. Then, twelve potential
derivatives were synthesized and characterized by IR, 1H-NMR, 13C-NMR, 19F-NMR
(for some compounds), and mass spectrometry. Derivatives 2cj and 1bj were the two molecules
having the best binding affinity of -11.9 and -11.8 kcal/mol, respectively, against MAOB,
exhibiting a higher binding affinity compared to that of some commercially available drugs.
A 50 ns MD simulation run was performed to observe the stability of the top two docked
complexes, MAO-B-2cj and MAO-B-1bj, in order to further validate the efficacy of those two
substances. Moreover, the MM-PBSA method was used to calculate the final, binding free energy
of the simulated (MAO-B-2cj) complex.
Conclusion::This study indicates that the binding affinity of most of the hits was superior to
that of known MAO inhibitors; therefore, these newly synthesized benzimidazole derivatives
may be developed into essential drug candidates for the treatment of PD.