Recent updates on structural insights of MAO-B inhibitors: a review on target-based approach

Abstract

Parkinson’s disease is a neurodegenerative disorder characterized by slow movement, tremors, and stiffness caused due to loss of dopaminergic neurons caused in the brain’s substantia nigra. The concentration of dopamine is decreased in the brain. Parkinson’s disease may be happened because of various genetic and environmental factors. Parkinson’s disease is related to the irregular expression of the monoamine oxidase (MAO) enzyme, precisely type B, which causes the oxidative deamination of biogenic amines such as dopamine. MAO-B inhibitors, available currently in the market, carry various adverse effects such as dizziness, nausea, vomiting, lightheadedness, fainting, etc. So, there is an urgent need to develop new MAO-B inhibitors with minimum side effects. In this review, we have included recently studied compounds (2018 onwards). Agrawal et al . reported MAO-B inhibitors with IC 50 0.0051 µM and showed good binding affinity. Enriquez et al . reported a compound with IC 50 144 nM and bind with some critical amino acid residue Tyr60, Ile198, and Ile199. This article also describes the structure–activity relationship of the compounds and clinical trial studies of related derivatives. These compounds may be used as lead compounds to develop potent compounds as MAO-B inhibitors. Graphic Abstract

Nitrogen‐containing heterocyclic compounds: A ray of hope in depression?

“…MAO-A and MAO-B inhibition prevents the breakdown of neurotransmitters and increases their respective concentrations in the synaptic cleft for neuronal signaling. Several classes of antidepressants are available (Figure 5) which include atypical antidepressants, monoamine oxidase inhibitors (MAOIs), serotoninnorepinephrine reuptake inhibitors (SNRIs), and SSRIs (Baweja et al, 2023;Dwyer & Bloch, 2019;Mannan et al, 2022;Nandi et al, 2023). Suryawanshi et al reported the rationale designing followed by synthesis and in silico studies of phenylacetamides derivatives (16a-y) as antidepressant agents.…”

New Insights on the Activity and Selectivity of MAO-B Inhibitors through In Silico Methods

“…The therapeutic capability of MAO's inhibitors, in conjunction with an exhaustive knowledge of the 3D structure of the MAO-B active site, may contribute to significant improvement in the development of novel drugs for Parkinson's disease. Recent updates on the design, synthesis, and clinical trials of new MAO candidates have been summarized in the paper of Baweja GS et al [13]. Even though numerous compounds have been continuously synthesized and clinically tested as possible candidates for treating PD, the dietary restrictions and adverse effects developed urgently require new theoretical, experimental, and therapeutic strategies to overcome these shortcomings.…”

“…In this context, cheminformatics approaches are systematically used in the early stages of drug development projects [11][12][13][14][15][16][17][18][19][20][21][22] and environmental science to assist the experiment in order to expedite and save resources and costs [23][24][25][26][27][28]. In silico tools can contribute significantly to exploring side effects by handling off-target interactions, which necessitates a thorough knowledge of structural information about off-target proteins [29][30][31][32][33].…”

“…In silico tools can contribute significantly to exploring side effects by handling off-target interactions, which necessitates a thorough knowledge of structural information about off-target proteins [29][30][31][32][33]. Theoretical and experimental studies included in the review of Baweja GS et al [13] pointed out that minor structural changes could significantly or detrimentally influence the selectivity and inhibitory activity of various derivatives as potential MAO-B inhibitors. The surveyed SAR analyses [13] underlined the key role of various substituents on the basic skeleton of coumarin, chalcone, piperazine-linked pyridazinone, 1,3,4-oxadiazole, thiosemicarbazide, pyridoxine-resveratrol, methylthiosemicarbazone, benzylamine-sulphonamide, isoxazole carbohydrazide and safinamide derivatives as MAO-B inhibitors.…”

“…Theoretical and experimental studies included in the review of Baweja GS et al [13] pointed out that minor structural changes could significantly or detrimentally influence the selectivity and inhibitory activity of various derivatives as potential MAO-B inhibitors. The surveyed SAR analyses [13] underlined the key role of various substituents on the basic skeleton of coumarin, chalcone, piperazine-linked pyridazinone, 1,3,4-oxadiazole, thiosemicarbazide, pyridoxine-resveratrol, methylthiosemicarbazone, benzylamine-sulphonamide, isoxazole carbohydrazide and safinamide derivatives as MAO-B inhibitors. For coumarin moiety-containing derivatives, the presence of hydroxy or halogen (Br, Cl) unit in position seven and halogen-substituted heterocyclics or substituted benzoxy unit increase the MAO-B activity [34][35][36].…”