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<p>Monoamine oxidase-B (MAO-B) plays a regulatory role in controlling the activity of monoamine neurotransmitters, especially dopamine. Its overexpression leads to a decreased concentration of dopamine in the brain, converts MPTP to MPP + (a potential toxin for dopaminergic neurons), and increases hydrogen peroxide and ROS levels in gliosis, leading to neurodegeneration. Thus, MAO-B becomes a key target enzyme for neurological disabilities such as PD and AD. In this study, we used drug repurposing to explore the pool of USFDA-approved and Pharmacopeial drugs (3619 drugs) and performed HTVS (high-throughput virtual screening) using both ADME parameters with emphasis on their ability to cross the BBB and considering the prerequisites of a generated pharmacophore model for MAO-B. The fetched 656 ligands were subjected to SP and XP dockings, MMGBSA, and dynamics analysis to identify the top 10 leads with maximum plausibility to interact with MAO-B. The analysis presented Bazedoxifene and Epicatechin as lead compounds with a higher affinity towards MAO-B than MAO-A. The in-silico work was further validated using in vitro biological analysis that includes MAO inhibitory activity, reversibility studies, and intracellular ROS inhibition studies. Epicatechin and bazedoxifene displayed moderate MAO-B inhibitory activities with IC<sub>50</sub> values of 11.14 ± 0.53&#xa0;µM and 13.11 ± 0.21&#xa0;µM, with more than sixfold and fourfold selectivity over MAO-A, respectively. Thus, this study can open the avenue to the development of Bazedoxifene and Epicatechin as potential pharmacophores for the design and development of selective and reversible MAO-B inhibitors with higher efficacy for the management of neurological disabilities.</p> Graphical abstract <p></p>

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Deploying the drug repurposing approach for the identification of selective monoamine oxidase-B inhibitors against neurological disabilities: an in Silico and in vitro approach

  • 期刊论文

  • 发表日期：

    2025年8月29日

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  • Mohamed Mohany,
  • Salim S. Al-Rejaie,
  • M. Arockia Babu,
  • Thakur Gurjeet Singh,
  • Prawez Alam,
  • Mohammad Fareed,
  • Nisha Bansal

摘要

Monoamine oxidase-B (MAO-B) plays a regulatory role in controlling the activity of monoamine neurotransmitters, especially dopamine. Its overexpression leads to a decreased concentration of dopamine in the brain, converts MPTP to MPP + (a potential toxin for dopaminergic neurons), and increases hydrogen peroxide and ROS levels in gliosis, leading to neurodegeneration. Thus, MAO-B becomes a key target enzyme for neurological disabilities such as PD and AD. In this study, we used drug repurposing to explore the pool of USFDA-approved and Pharmacopeial drugs (3619 drugs) and performed HTVS (high-throughput virtual screening) using both ADME parameters with emphasis on their ability to cross the BBB and considering the prerequisites of a generated pharmacophore model for MAO-B. The fetched 656 ligands were subjected to SP and XP dockings, MMGBSA, and dynamics analysis to identify the top 10 leads with maximum plausibility to interact with MAO-B. The analysis presented Bazedoxifene and Epicatechin as lead compounds with a higher affinity towards MAO-B than MAO-A. The in-silico work was further validated using in vitro biological analysis that includes MAO inhibitory activity, reversibility studies, and intracellular ROS inhibition studies. Epicatechin and bazedoxifene displayed moderate MAO-B inhibitory activities with IC50 values of 11.14 ± 0.53 µM and 13.11 ± 0.21 µM, with more than sixfold and fourfold selectivity over MAO-A, respectively. Thus, this study can open the avenue to the development of Bazedoxifene and Epicatechin as potential pharmacophores for the design and development of selective and reversible MAO-B inhibitors with higher efficacy for the management of neurological disabilities.

Graphical abstract