Additionally, docking studies suggest the phenyl side groups of Tyr407 and Tyr444 (for MAO-A) or Tyr398 and Tyr435 (for MAO-B) play an important role in the interaction of the enzyme with 1,4-NQ scaffold through forces of dispersion as verified for menadione, TMN and 1,4-NQ. Fluorescence and molecular modeling data indicated that these inhibitors interact with the flavin moiety at the active site of the enzyme. Contrasting with TMN and 1,4-NQ, menadione exhibited a 60-fold selectivity for MAO-B (K(i)=0.4 μM) in comparison with MAO-A (K(i)=26 μM), which makes it as selective as rasagiline. Herein we show that MAO-B was inhibited competitively by 1,4-NQ (K(i)=1.4 μM) whereas MAO-A was inhibited by non-competitive mechanism (K(i)=7.7 μM). Menadione (2-methyl-1,4-naphthoquinone) is a multitarget drug that acts as a precursor of vitamin K and an inducer of mitochondrial permeability transition. Combining molecular modeling tools and biochemical assays we evaluate the kinetic and molecular details of the inhibition of human MAO by 1,4-NQ, comparing it with TMN and menadione. The discovery of 2,3,6-trimethyl-1,4-naphthoquinone (TMN) as a nonselective and reversible inhibitor of MAO, has suggested 1,4-naphthoquinone (1,4-NQ) as a potential scaffold for designing new MAO inhibitors. Monoamine oxidase ( MAO) catalyzes the oxidative deamination of biogenic and exogenous amines and its inhibitors have therapeutic value for several conditions including affective disorders, stroke, neurodegenerative diseases and aging. Molecular insights into human monoamine oxidase ( MAO) inhibition by 1,4-naphthoquinone: evidences for menadione (vitamin K3) acting as a competitive and reversible inhibitor of MAO.Ĭoelho Cerqueira, Eduardo Netz, Paulo Augusto Diniz, Cristiane Petry do Canto, Vanessa Follmer, Cristian The slightly different binding pose of 18 into the MAO-B active site seems to be forced by a bulkier Tyr residue, which replaces a smaller Ile residue present in MAO-A. In contrast, compound 7 places its phenyl ring into an aromatic cage of the MAO-B binding pocket, where it forms charge-transfer interactions. This H-bond is absent in the 7/ MAO-A complex. Compound 18 forms an H-bond with Gln215 through its protonated amino group into the MAO-A binding site. Docking and molecular dynamics simulations gave structural insights into the MAO-A and MAO-B selectivity. N-Methyl,N-(benzyl),N-(pyrrol-2-ylmethyl)amine (7) and N-(2-benzyl),N-(1-methylpyrrol-2-ylmethyl)amine (18) were the most selective MAO-B (7, SI = 0.0057) and MAO-A (18, SI = 12500) inhibitors, respectively. La Regina, Giuseppe Silvestri, Romano Artico, Marino Lavecchia, Antonio Novellino, Ettore Befani, Olivia Turini, Paola Agostinelli, EnzoĪ series of new pyrrole derivatives have been synthesized and evaluated for their monoamine oxidase ( MAO) A and B inhibitory activity and selectivity. New pyrrole inhibitors of monoamine oxidase: synthesis, biological evaluation, and structural determinants of MAO-A and MAO-B selectivity. Thus has a dual function for both therapy and diagnosis. NMI can also be used as a non-invasive imaging tool. In conclusion, we have identified MAO A inhibitors as potential novel stand-alone drugs or as combination therapy with low dose TMZ for drug-resistant gliomas. Immunocytochemistry studies showed that the MAO A inhibitor reduced proliferation, microvessel density and invasion, and increased macrophage infiltration. NMI was localized specifically to the tumor. Using the intracranial TMZ-resistant glioma model, clorgyline or NMI alone or in combination with low-dose TMZ reduced tumor growth and increased animal survival. MAO A inhibitors, clorgyline or the near-infrared-dye MHI-148 conjugated to clorgyline (NMI), were cytotoxic for glioma and decreased invasion in vitro. This study shows that MAO A expression is increased in human glioma tissues and cell lines. Monoamine Oxidase A ( MAO A) oxidizes monoamine neurotransmitters resulting in reactive oxygen species which cause cancer. Tumors usually become resistant to TMZ and recur no effective therapy is then available. Glioblastoma (GBM) is an aggressive brain tumor which is currently treated with temozolomide (TMZ). Vaikari, Vijaya Pooja Kota, Rajesh Chen, Kevin Yeh, Tzu-Shao Jhaveri, Niyati Groshen, Susan L. Monoamine oxidase A ( MAO A) inhibitors decrease glioma progression
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