Introduction: Neurochemical alterations in monoaminergic neurotransmission are
common manifestations in neurological disorders, such as neurodegenerative
diseases, as well as psychiatric disorders like depression and schizophrenia. The
enzyme monoamine oxidase B (MAO-B) serves as a significant pharmacological target
due to its physiological role in terminating monoaminergic neurotransmission. In this
context, MAO-B inhibitors represent therapeutic alternatives aimed at increasing the
availability of monoamines in synaptic clefts in cases of serotonin, dopamine,
norepinephrine, and epinephrine decrease/depletion, providing potential treatments for
neuropsychiatric disorders that share genetic or neurobiological pathways related to
neurological and psychiatric symptoms. Objective: To perform a virtual screening of
molecules with potential inhibitory activity on MAO-B using computational tools.
Materials and Methods: A pharmacophore model was built using the Pharmagist
platform based on potent MAO-B inhibitors extracted from the BindingDB database.
This model was used to search for molecules with similar physicochemical properties
in the ZincPharmer database. Conformers of the molecules obtained were then
generated using the OMEGA software to assess the influence of structural aspects on
their bioactivity. This was followed by screening using electrostatic and structural
filters, considering the selective MAO-B inhibitor safinamide in the EON and ROCS
software. Further screening for binding affinity probability was conducted using the
GOLD software, and the most promising and safest molecules were identified through
in silico toxicity assays using the DEREK software, pharmacokinetic predictions in
QikProp, and drug interaction predictions using the SwissADME platform. Results and
Discussion: The pharmacophore-based search identified 10,000 molecules in
ZincPharmer. After screenings with various computational tools, the following
compounds were discovered: 1-[[2-(difluoromethoxy)phenyl]methyl]-4-(pyrrolo[3,2-
b]pyridin-1-ylmethyl)piperidin-4-ol (ligand 775), 3-[2-(1,3-benzodioxol-5-yl)-2-
oxoethyl]-6-bromoquinazolin-4-one (ligand 984), 6-chloroimidazo[1,2-a]pyridin-2-yl-[4-
(2-pyrazol-1-ylethyl)piperidin-1-yl]methanone (ligand 596), and (2-phenylimidazo[1,2-
a]pyridin-6-yl)-[(2R)-2-pyridin-2-ylpyrrolidin-1-yl]methanone (ligand 627). These
molecules exhibit structural, physicochemical, pharmacokinetic properties, and
interaction profiles with MAO-B characteristic of selective and reversible inhibitors
targeting the selected enzyme. Conclusions: The ligands identified through the in
silico screening are promising substances for further validation in preclinical studies,
aiming to better understand their pharmacological and toxicological properties, with
potential for clinical application.