Article pubs.acs.org/JAFC
Inhibition of Human Monoamine Oxidase: Biological and Molecular Modeling Studies on Selected Natural Flavonoids Simone Carradori,*,† Maria Concetta Gidaro,§ Anél Petzer,# Giosuè Costa,§ Paolo Guglielmi,⊥ Paola Chimenti,⊥ Stefano Alcaro,§ and Jacobus P. Petzer# †
Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy Dipartimento di Scienze della Salute, “Magna Graecia” University of Catanzaro, Campus Universitario “S. Venuta”, Viale Europa Loc. Germaneto, 88100 Catanzaro, Italy # Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2531, South Africa ⊥ Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy
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S Supporting Information *
ABSTRACT: Naturally occurring flavonoids display a plethora of different biological activities, but emerging evidence suggests that this class of compounds may also act as antidepressant agents endowed with multiple mechanisms of action in the central nervous system, increasing central neurotransmission, limiting the reabsorption of bioamines by synaptosomes, and modulating the neuroendocrine and GABAA systems. Due to their presence in foods, food-derived products, and nutraceuticals, we established their role and structure−activity relationships as reversible and competitive human monoamine oxidase (MAO) inhibitors. In addition, molecular modeling studies, which evaluated their modes of MAO inhibition, are presented. These findings could provide pivotal implications in the quest of novel drug-like compounds and for the establishment of harmful drug−dietary supplement interactions commonly reported in the therapy with antidepressant agents. KEYWORDS: monoamine oxidase inhibitor, apigenin, taxifolin, diosmetin, naringin, eriocitrin, isorhamnetin, hesperidin, quercetin-3-O-glucoside
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INTRODUCTION Human monoamine oxidases (hMAO-A and hMAO-B; EC 1.4.3.4) are mitochondrial enzymes that oxidatively deaminate monoaminergic neurotransmitters and (potentially harmful) dietary monoamines. In the brain, their main role is the regulation of important monoamines such as noradrenaline, dopamine, serotonin, and adrenaline. The hMAO-A isoform is present in catecholaminergic neurons and degrades sterically hindered amines such as serotonin, adrenaline, and noradrenaline; hMAO-B is mainly abundant in the periventricular region of the hypothalamus and the substantia nigra, where it metabolizes small monoamines such as β-phenethylamine and benzylamine. Both isoforms use dopamine and p-tyramine as common substrates.1 Due to their crucial physiological roles, the hMAO-A isoform is an established pharmacological target for the therapy of (resistant and atypical) depression, anxiety disorders, dysthymia, and major depressive disorder, whereas the hMAO-B isoform is a target for the treatment of neurodegenerative disorders including Parkinson’s disease and Alzheimer’s disease. Moreover, selective hMAO-B inhibitors have been shown to protect neurons against degeneration by means of anti-apoptotic mechanisms, the reduction of reactive oxygen species, and the stabilization of the mitochondria.2 A plethora of molecules of natural origin have been shown to inhibit the hMAOs and, in addition, different synthetic scaffolds have often been inspired by natural products such as flavonoids, coumarins, purine derivatives, and alkaloids.3−6 Secondary metabolites from plants are frequently used by medicinal chemists in © 2016 American Chemical Society
an attempt to design simple small molecules that mimic the heterogeneity of scaffolds found in natural products. Moreover, there has been an interest in traditional flavonoid-enriched herbal medicines because of their application for the therapy of specific disorders.7−11 Exact knowledge of the molecular mechanism of action of several natural products, which could be ingested daily through the diet in gram amounts, could be important to avoid or limit harmful food−food and drug−food interactions. Flavonoids could be classified as plant polyphenolic metabolites responsible for specific effects in promoting human health and modulating physiological functions, which depend on the substitution pattern and related chemical−physical properties.12−14 Indeed, these compounds are characterized by a highly reactive hydroxyl moiety, which acts as a free radical scavenger by means of oxidation to a less reactive molecule, thus preventing ailments associated with oxidative stress. These compounds also trigger important enzymes involved in mitochondrial respiration and chelate divalent metal ions. Emerging evidence suggests that flavonoids may possess antidepressant activity by acting via multiple mechanisms to increase monoamine neurotransmission in the brain. These mechanisms include inhibition of the reabsorption of bioamines by synaptosomes and modulation of the neuroendocrine and GABAA systems.15,16 Received: Revised: Accepted: Published: 9004
August 5, 2016 November 9, 2016 November 9, 2016 November 9, 2016 DOI: 10.1021/acs.jafc.6b03529 J. Agric. Food Chem. 2016, 64, 9004−9011
Article
Journal of Agricultural and Food Chemistry
known inhibitors of human and rat liver MAO.8,17 Taxifolin (3) and isorhamnetin (4) possess an additional OH moiety on C3. Moreover, due to numerous reports of the MAO inhibition properties of quercetin, we also studied its 3-O-glucosidic derivative, isoquercitrin (5), which displayed an IC50 of 11.64 μM for the inhibition of bovine brain MAO-B.17 Finally, naringin (6), eriocitrin (7), and hesperidin (8) are flavanones characterized by different bulky diglycosidic substituents on C7. After the determination of their MAO inhibitory activity and kinetics in vitro, we also performed docking simulations and molecular dynamics studies to investigate the mechanism of action and ligand−target interactions for these widely distributed flavonoids.
Recently, we analyzed the structure−activity relationships (SARs) of this class of natural compounds as MAO inhibitors and investigated their antidepressant-like effects in animal models.17,18 Generally, the increasing number of −OH groups on the aromatic ring of this scaffold decreased the MAO inhibitory activity. Moreover, the introduction of a sugar or glucuronic acid at C7 lowered this biological activity. MAO inhibition is strongly dependent on the presence of a (p-OHsubstituted)phenyl at C2, unsaturation at the C2−C3 positions of the structure, the possibility of establishing hydrophobic interactions, and ring planarity. These polar plant metabolites can cross the blood−brain barrier due to their cLogP values ranging from 1.5 to 3.5 and because they were shown to induce biological effects directly in the central nervous system (CNS).17 Among natural flavonoid compounds, we selected the most abundant and representative derivatives and evaluated them as potential hMAO inhibitors in an attempt to improve and corroborate SARs for their target interaction (Figure 1). Apigenin (1) and diosmetin (2) are 2,5,7-trisubstituted flavones, which are
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MATERIALS AND METHODS
All commercial samples of selected flavonoids (apigenin ≥99%, diosmetin ≥98%, taxifolin ≥98%, isorhamnetin ≥99%, isoquercitrin ≥98%, naringin ≥95%, eriocitrin ≥98%, hesperidin ≥97%) and reference drugs (harmine 98%, safinamide mesylate salt ≥98%) were purchased from Sigma-Aldrich (Milan, Italy).
Figure 1. Structures of the selected flavonoids (1−8) assayed as hMAO inhibitors. 9005
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Journal of Agricultural and Food Chemistry Microsomes from insect cells containing recombinant hMAOs (5 mg/mL) were used as sources of the MAO enzymes. These isoenzymes, kynuramine, (R)-deprenyl, and pargyline, were supplied by Sigma-Aldrich (St. Louis, MO, USA). The Prism 5 software package (GraphPad Software, La Jolla, CA, USA) was chosen for data analyses and for the construction of graphs. Fluorescence spectrophotometry was carried out with a Varian Cary Eclipse fluorescence spectrophotometer (Agilent Technologies, Santa Clara, CA, USA). For the computational studies, the following commercial softwares were used: Maestro, version 9.7 (Schrödinger, LLC, New York, NY, USA); LigPrep, version 2.9 (Schrödinger, LLC); Glide, version 6.2 (Schrödinger, LLC); Desmond Molecular Dynamics System, version 3.7 (D. E. Shaw Research, New York, NY, USA); Maestro-Desmond Interoperability Tools, version 3.7 (Schrödinger LLC); PyMOL Molecular Graphics System, version 1.7.0.0 (Schrödinger, LLC). Biochemistry. Measurement of IC50 and Ki Values. IC50 values for the inhibition of hMAO-A and hMAO-B were determined according to the published protocol.19 The experimental protocol was performed in 96-well microtiter plates (white) to a final volume of 200 μL. The reactions contained kynuramine (50 μM), different concentrations of the test inhibitors (0.003−100 μM), and DMSO (4%) as cosolvent. Potassium phosphate buffer (100 mM, pH 7.4, made isotonic with KCl) was used as reaction solvent. The enzymatic reactions were initiated with the addition of hMAO-A (0.0075 mg protein/mL) or hMAO-B (0.015 mg protein/mL) and, after 20 min of incubation at 37 °C, were terminated with the addition of sodium hydroxide (80 μL of 2 N). The MAO-generated metabolite, 4-hydroxyquinoline, was subsequently quantitated by fluorescence spectrophotometry (λex = 310; λem = 400 nm). For this purpose, linear calibration curves constructed with 4-hydroxyquinoline (0.047−1.56 μM) were employed. After fitting the inhibition data to the one-site competition model incorporated into the Prism 5 software package, the IC50 values were calculated. These are expressed as the mean ± standard deviation (SD) of triplicate determinations (three replicates of one concentration range). To calculate Ki values for the inhibition of hMAOs, Lineweaver−Burk plots were accomplished. For each inhibitor, a set of six plots was constructed using the following inhibitor concentrations: 0, 0.25, 0.5, 0.75, 1.0, and 1.25 × IC50, respectively. For each plot, eight different concentrations of kynuramine were employed (15−250 μM). The enzymatic reactions and fluorometric measurements were conducted as previously described with the exception that the concentration of both hMAO-A and hMAO-B was 0.015 mg protein/mL. Moreover, these experiments were performed in a final volume of 500 μL and, after termination with NaOH (400 μL of 2 N), 1 mL of water was added and the resulting samples were quantitated by fluorescence spectrophotometry (using a 3.5 mL quartz cuvette). The Ki values were estimated from replots of the slopes of the Lineweaver− Burk plots versus inhibitor concentration (−Ki = x-axis intercept) as well as by global fitting of the inhibition data to the Michaelis−Menten equation using the Prism 5 software package. Dialysis Studies. Dialysis of mixtures containing the hMAOs and test inhibitors was carried out using Slide-A-Lyzer dialysis cassettes (Thermo Scientific, Waltham, MA, USA) with a molecular weight cutoff of 10,000 and a sample volume capacity of 0.5−3 mL. This protocol has been reported previously.20 The hMAOs (0.03 mg protein/mL) were incubated with the test inhibitors, apigenin (1) and diosmetin (2), as well as with the reference irreversible inhibitors, pargyline (IC50 = 13 μM) and (R)-deprenyl (IC50 = 0.079 μM), for 15 min at 37 °C. For these experiments, the inhibitor concentrations were 4 × IC50, and the final volume was 0.8 mL. Control incubations were also evaluated in the absence of inhibitor. The incubation mixtures were dialyzed using potassium phosphate buffer (100 mM, pH 7.4, containing 5% sucrose) as dialysis buffer (80 mL). The dialysis buffer was replaced with fresh buffer at 3 and 7 h after the start of dialysis. Following dialysis, the mixtures were diluted 2-fold with the addition of kynuramine to obtain a substrate concentration equal to 50 μM and an inhibitor concentration of 2 × IC50. The final volume of these reactions was 500 μL, and the residual hMAO activities were measured as described for the measurement of Ki values above. For comparison, nondialyzed incubation mixtures containing the hMAOs
Table 1. IC50 Values for the Inhibition of hMAO-A and hMAO-B by Selected Flavonoids 1−8 and Reference Drugs compound 1 2 3 4 5 6 7 8 harmine safinamide a
hMAO-A inhibitiona (μM) 1.55 5.74 >100 64.2 >100 33.3 86.5 >100 0.0029 112
± 0.147 ± 0.571 ± 7.69 ± 7.05 ± 32.4 ± 0.00042 ± 5.23
hMAO-B inhibitiona (μM) 5.16 1.58 >100 21.2 >100 44.6 164 >100 >100 0.048
± 0.410 ± 0.887 ± 4.99 ± 11.2 ± 39.2
± 0.0047
The values are given as the mean ± SD of triplicate determinations.
Figure 2. Dialysis restores the activities of the hMAOs following inhibition by (A) apigenin (1) and (B) diosmetin (2). Dialysis, however, does not restore the hMAO activities following inhibition by the irreversible inhibitors, pargyline (parg) and (R)-deprenyl (depr). NI, no inhibitor. (∗) Statistically significantly different from the mean of inhibitor-dialyzed. The values are given as the mean ± SD of triplicate determinations. and 1 or 2 were maintained at 4 °C for 24 h and diluted 2-fold, and the residual enzyme activity measured. The hMAO activities are reported as the mean ± SD of triplicate determinations. The Kruskal−Wallis test with Dunn’s post hoc test was used to determine the statistical differences among the means of the residual enzyme rates. A p value 100 μM) against both isoforms, whereas the diglycosidic derivatives (6−8) exhibited relatively low hMAO inhibitory activity compared to the most potent flavonoids of the series, 1 and 2. Collectively, all selected natural flavonoids were less potent than the reference drugs, harmine and safinamide. As evident from the IC50 values, both safinamide (MAO-B inhibitor) and harmine (MAO-A inhibitor) are high-potency inhibitors of the respective MAO isoforms. Also evident is the fact that these reference inhibitors are highly specific, with safinamide acting as a MAO-B inhibitor and harmine as a MAO-A inhibitor. To better characterize the inhibition mode of the two most potent flavonoid hMAO inhibitors, 1 and 2 were incubated with hMAOs at concentrations equal to 4 × IC50 and subsequently dialyzed for 24 h.27 The irreversible MAO-A and MAO-B inhibitors, pargyline and (R)-deprenyl, were similarly incubated and dialyzed and served as positive controls. As negative control, the hMAOs were dialyzed in the absence of inhibitor. 9008
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Figure 5. Best orientations into the hMAO-B catalytic site of (A) apigenin (1) and (B) diosmetin (2), displayed as orange and violet sticks, respectively. The FAD cofactor is shown as cyan sticks, whereas the amino acid residues that are involved in ligand−target interactions are shown as cyan lines. The hMAO proteins are represented as cyan surfaces and cartoons. All non-carbon atoms are colored according to atom types.
−9.09 and −8.73 kcal/mol, respectively. Moreover, 2 displayed a binding affinity for hMAO-B of −9.21 kcal/mol, which is higher than the binding affinity to hMAO-A (−8.48 kcal/mol). The reversal of the isoform selectivity of 2 compared to that of 1 may be explained by taking into account the different mechanism of recognition observed during the in silico studies. As often remarked, the amino acid residues in the area opposite the FAD cofactor (hMAO-A, I180, N181, F208, S209, and I335 with the corresponding hMAO-B residues, L171, C172, I199, S200, and Y326, respectively) define the shapes of the active sites with the hMAO-A active binding site being smaller and broader than the elongated and narrower one of hMAO-B.32 Therefore, the docking study shows that in hMAO-A, both flavonoids bind with the flavonoid portion oriented toward the FAD cofactor, whereas the phenyl substituents extend toward the active site entrance (Figure 4). In hMAO-B, 2 exhibits a similar positioning, whereas 1 binds in a reversed orientation (Figure 5). The different binding orientations in hMAO-B may explain the different isoform selectivities of 1 and 2. As reported in our previous work, bulky natural compounds such as crocin may inhibit the hMAOs noncompetitively by possibly interacting with an allosteric site of the enzyme surface.33 In this study, we observed that the two glycosidic derivatives, 6 and 7, which are modest hMAO inhibitors, also bind to a site that is distant from the substrate binding cavity (Table 1 and Figure 6). Therefore, molecular dynamics studies were carried out for the complexes of hMAO-A/B with 1 and 2 to further investigate ligand−target interactions established with residues defining the binding pocket and with 6 and 7 to
Figure 6. Molecular recognition of (A) naringin (6) and (B) eriocitrin (7), shown as blue and yellow sticks, respectively, by a binding site distal from the catalytic site of the hMAOs. The hMAO proteins are displayed as transparent surfaces, and the FAD cofactors are shown as gray sticks in hMAO-A and cyan sticks in hMAO-B, respectively. All non-carbon atoms of the ligands are colored according to atom types.
Natural and synthetic coumarin derivatives, which are structurally related to flavonoids, are known to inhibit the hMAOs28−31 and, in particular, the MAO-B isoform. Two X-ray crystal structures of hMAO-B cocrystallized with coumarin derivatives are available in the Protein Data Bank21 (accession codes 2V60 and 2V61). However, to perform the docking simulations, we selected the X-ray crystal structures of the hMAOs in complex with the reference compounds used in this study. Therefore, hMAO-A/harmine and hMAO-B/safinamide complexes were obtained (accession codes 2Z5X22 and 2V5Z,23 respectively). The results of the modeling studies show that 1 and 2 bind competitively with the best poses docked into the catalytic site of the enzymes (Figures 4 and 5). The theoretical results confirmed that 1 is better accommodated in the hMAO-A active site than in that of hMAO-B, with Gscore values of 9009
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Journal of Agricultural and Food Chemistry explore target stabilization by a binding site that is distal from the catalytic site. The molecular dynamics results suggest that the glycosidic flavonoids do not fit into the binding pockets of the hMAOs due to steric hindrance. Stabilization of complexes is mainly attributed to several H-bond contacts involving −OH groups of the sugar portions and the protein residues. In contrast, within the hMAOs catalytic sites, which are defined by mostly hydrophobic amino acid residues, 1 and 2 establish a great number of hydrophobic contacts with key residues as well as several H-bond contacts. As a possible explanation for the higher selectivity of 1 for the hMAO-A compared to 2, the molecular dynamics results revealed that 1 establishes a great number of H-bond/hydrophobic contacts, whereas for 2, which is disubstituted on the phenyl, ligand−target interactions are limited due to intramolecular bonding between the ortho −OH and −OCH3 groups (Table 1). In conclusion, identification of (selective) hMAO inhibitors is of much interest for the therapy of diseases affecting the CNS and to avoid possible interactions with other serotonergic drugs (serotonin syndrome) and foods rich in dietary monoamines (cheese effect). Dietary restrictions are strictly mandatory for patients under therapy with MAO inhibitors. For this reason, we assessed the hMAO inhibitory properties of the most important and abundant flavone (1−5) and flavanone (6−8) derivatives and investigated the binding modes of selected derivatives to the hMAOs by molecular modeling studies for the first time. Flavonoids that are active MAO inhibitors are abundantly present in many foods. For example, 1 occurs in many common vegetables and fruits such as parsley, grapefruit, orange, and onions and is also present in plant-derived beverages, such as chamomile tea.34 Due to their role as hMAO inhibitors, these natural compounds may be useful for the treatment of motor symptoms in the early stages of neurodegenerative diseases.35
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ABBREVIATIONS USED
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REFERENCES
CNS, central nervous system; hMAO, human monoamine oxidase; SARs, structure−activity relationships; PDB, Protein Data Bank; SID, simulation interactions diagram; Gscore, glide scoring function
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jafc.6b03529. Table 1S, theoretical affinities of the selected flavonoids for the hMAOs. Figures 1S−4S, summaries of MD simulations for the complexes of hMAO-A/B with apigenin (1), diosmetin (2), naringin (6), and eriocitrin (7), respectively (PDF)
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AUTHOR INFORMATION
Corresponding Author
*(S.C.) Phone/fax: +39 0871 3554583. E-mail: simone.
[email protected]. ORCID
Simone Carradori: 0000-0002-8698-9440 Funding
This research was funded by “Progetto di Ateneo Ricerca 2013” (P. Chimenti) and the Interregional Research Center for Food Safety and Health at the Magna Græcia University of Catanzaro (MIUR PON a3_00359). Notes
The authors declare no competing financial interest. 9010
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