# The discovery of monoamine oxidase inhibitors: virtual screening and in vitro inhibition potencies

## TL;DR

This study uses virtual screening to find new inhibitors of monoamine oxidase enzymes, which are important in treating brain disorders like depression and Parkinson's.

## Contribution

The study introduces a validated virtual screening protocol for identifying MAO inhibitors using DrugBank and evaluates its effectiveness with in vitro testing.

## Key findings

- Guanabenz and proflavine were identified as potent MAO-A inhibitors with IC50 values of 3.46 µM and 0.223 µM, respectively.
- The LibDock/LigScore 2 combination showed the best performance in virtual screening for both MAO-A and MAO-B.
- Proflavine exhibited a competitive mode of inhibition with a Ki value of 0.066 µM for MAO-A.

## Abstract

The monoamine oxidase (MAO) enzymes are mitochondrial flavoenzymes that catalyse the oxidative deamination of neurotransmitter amines such as serotonin, norepinephrine and dopamine. Inhibitors of the MAOs are well-known antidepressant and antiparkinsonian agents, and act by reducing MAO-mediated metabolism of neurotransmitters in the brain. The present study attempted to identify compounds that inhibit the MAOs by virtual screening of existing drugs listed in the DrugBank using the Discovery Studio life science software. To identify the combinations of docking and scoring functions that most accurately identify known MAO inhibitors, the enrichment factor (EF10%) and area under the receiver operating characteristic curve (ROC-AUC) were evaluated. As a third validation metric, ligands that have been complexed with the MAOs were redocked and the root mean square deviation (RMSD) from the co-crystallized orientation was measured. The LibDock/LigScore 2 combination yielded the best results for both MAO-A (EF10%: 5.20, ROC-AUC: 0.82) and MAO-B (EF10%: 7.47, ROC-AUC: 0.89). Among the top 100 hits, ten compounds were selected and evaluated as in vitro inhibitors of human MAO. Guanabenz (IC50 = 3.46 µM) and proflavine (IC50 = 0.223 µM) were found to be the most potent MAO-A inhibitors. These compounds also inhibited MAO-B with IC50 values of 8.49 and 34.3 µM, respectively. Kinetic analysis showed a competitive mode of MAO-A inhibition for guanabenz (Ki = 0.16 µM) and proflavine (Ki = 0.066 µM). These results show that the validated virtual screening protocol is a useful tool to aid in the discovery of MAO inhibitors.

The online version contains supplementary material available at 10.1007/s10822-026-00764-y.