The catechol-O-methyltransferase inhibitory potential of Z-vallesiachotamine by in silico and in vitro approaches

Passos, Carolina dos Santos; Klein‐Júnior, Luiz Carlos; Andrade, Juliana Maria de Mello; Matté, Cristiane; Henriques, Amélia Teresinha

doi:10.1016/j.bjp.2015.07.002

Cited by 11 publications

(5 citation statements)

References 30 publications

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“…Stimulated by the research on Ayahuasca, further Psychotria species became the subject of pharmacological and pharmacobotanical studies. Several indole alkaloids have been isolated and evaluated regarding their bioactivity on proteins related to Alzheimer’s disease (AD) and Parkinson’s disease (PD) ( Passos et al, 2013 ; dos Santos Passos et al, 2015 ; Klein-Júnior et al, 2016 , 2017 , 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Azepine-Indole Alkaloids From Psychotria nemorosa Modulate 5-HT2A Receptors and Prevent in vivo Protein Toxicity in Transgenic Caenorhabditis elegans

et al. 2022

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Nemorosine A (1) and fargesine (2), the main azepine-indole alkaloids of Psychotria nemorosa, were explored for their pharmacological profile on neurodegenerative disorders (NDs) applying a combined in silico–in vitro–in vivo approach. By using 1 and 2 as queries for similarity-based searches of the ChEMBL database, structurally related compounds were identified to modulate the 5-HT2A receptor; in vitro experiments confirmed an agonistic effect for 1 and 2 (24 and 36% at 10 μM, respectively), which might be linked to cognition-enhancing properties. This and the previously reported target profile of 1 and 2, which also includes BuChE and MAO-A inhibition, prompted the evaluation of these compounds in several Caenorhabditis elegans models linked to 5-HT modulation and proteotoxicity. On C. elegans transgenic strain CL4659, which expresses amyloid beta (Aβ) in muscle cells leading to a phenotypic paralysis, 1 and 2 reduced Aβ proteotoxicity by reducing the percentage of paralyzed worms to 51%. Treatment of the NL5901 strain, in which α-synuclein is yellow fluorescent protein (YFP)-tagged, with 1 and 2 (10 μM) significantly reduced the α-synuclein expression. Both alkaloids were further able to significantly extend the time of metallothionein induction, which is associated with reduced neurodegeneration of aged brain tissue. These results add to the multitarget profiles of 1 and 2 and corroborate their potential in the treatment of NDs.

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Section: Introductionmentioning

confidence: 99%

Azepine-Indole Alkaloids From Psychotria nemorosa Modulate 5-HT2A Receptors and Prevent in vivo Protein Toxicity in Transgenic Caenorhabditis elegans

et al. 2022

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“…It seems that molecular interactions between phytochemicals and COMT at the active site play a significant role in the inhibitory potency. The lack of hydrogen bond interactions observed in the case of the non-catecholic indole alkaloid Z -vallesiachotamine explains its high IC 50 value of 196 µM [ 26 ]. Submicromolar range IC 50 values observed with chlorogenic acid and (-)-epigallocatechin-3-gallate were explained by the more stable conformation through the hydrogen bonding networks between structurally flexible hydroxyl groups of the ligand and Asn170 or Lys144 at the COMT active site [ 17 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

Nordihydroguaiaretic Acid as a Novel Substrate and Inhibitor of Catechol O-Methyltransferase Modulates 4-Hydroxyestradiol-Induced Cyto- and Genotoxicity in MCF-7 Cells

et al. 2021

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Nordihydroguaiaretic acid (NDGA) is a major lignan metabolite found in Larrea spp., which are widely used in South America to treat various diseases. In breast tissue, estradiol is metabolized to the catechol estrogens such as 4-hydroxyestradiol (4-OHE2), which have been proposed to be cancer initiators potentially involved in mammary carcinogenesis. Catechol-O-methyltransferase (COMT) catalyzes the O-methylation of catechol estrogens to their less toxic methoxy derivatives, such as 4-O-methylestradiol (4-MeOE2). The present study investigated the novel biological activities of NDGA in relation to COMT and the effects of COMT inhibition by NDGA on 4-OHE2-induced cyto- and genotoxicity in MCF-7 human breast cancer cells. Two methoxylated metabolites of NDGA, 3-O-methylNDGA (3-MNDGA) and 4-O-methyl NDGA (4-MNDGA), were identified in the reaction mixture containing human recombinant COMT, NDGA, and cofactors. Km values for the COMT-catalyzed metabolism of NDGA were 2.6 µM and 2.2 µM for 3-MNDGA and 4-MNDGA, respectively. The COMT-catalyzed methylation of 4-OHE2 was inhibited by NDGA at an IC50 of 22.4 µM in a mixed-type mode of inhibition by double reciprocal plot analysis. Molecular docking studies predicted that NDGA would adopt a stable conformation at the COMT active site, mainly owing to the hydrogen bond network. NDGA is likely both a substrate for and an inhibitor of COMT. Comet and apurinic/apyrimidinic site quantitation assays, cell death, and apoptosis in MCF-7 cells showed that NDGA decreased COMT-mediated formation of 4-MeOE2 and increased 4-OHE2-induced DNA damage and cytotoxicity. Thus, NDGA has the potential to reduce COMT activity in mammary tissues and prevent the inactivation of mutagenic estradiol metabolites, thereby increasing catechol estrogen-induced genotoxicities.

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“…Particularly, compound 28 displayed a binding pose very identical to 3,5-dinitrocatechol and shared some common interactions with the residues Trp38, Trp143 and Lys144 as well, indicating that with refined structure modifications a potential drug candidate could be designed [143]. Similar strategies were employed by other research groups to investigate the interactions formed in the COMT active site with other compounds like rosmarinic acid (PDB#3BWM) [144], vallesiachotamine (PDB#3BWM) [145], 7,8-dihydroxycoumarins (PDB#3BWY) [146], and oleacein (PDB#3BWM) (Figure 23), which combined docking with molecular dynamics simulations [147]. site is surrounded by the "gatekeeper" residues Trp43 and Pro174, which ensure the correct orientation of the substrate, the magnesium ion and the S-(5′-Adenosyl)-L-methionine (SAM) cofactors, as well as residues Trp143, Lys144, and Glu199, which are involved in substrate binding [141].…”

Section: Catechol-o-methyltransferase Inhibitorsmentioning

confidence: 94%

Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches

et al. 2021

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Neurodegenerative diseases (ND), including Alzheimer’s (AD) and Parkinson’s Disease (PD), are becoming increasingly more common and are recognized as a social problem in modern societies. These disorders are characterized by a progressive neurodegeneration and are considered one of the main causes of disability and mortality worldwide. Currently, there is no existing cure for AD nor PD and the clinically used drugs aim only at symptomatic relief, and are not capable of stopping neurodegeneration. Over the last years, several drug candidates reached clinical trials phases, but they were suspended, mainly because of the unsatisfactory pharmacological benefits. Recently, the number of compounds developed using in silico approaches has been increasing at a promising rate, mainly evaluating the affinity for several macromolecular targets and applying filters to exclude compounds with potentially unfavorable pharmacokinetics. Thus, in this review, an overview of the current therapeutics in use for these two ND, the main targets in drug development, and the primary studies published in the last five years that used in silico approaches to design novel drug candidates for AD and PD treatment will be presented. In addition, future perspectives for the treatment of these ND will also be briefly discussed.

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The catechol-O-methyltransferase inhibitory potential of Z-vallesiachotamine by in silico and in vitro approaches

Cited by 11 publications

References 30 publications

Azepine-Indole Alkaloids From Psychotria nemorosa Modulate 5-HT2A Receptors and Prevent in vivo Protein Toxicity in Transgenic Caenorhabditis elegans

Azepine-Indole Alkaloids From Psychotria nemorosa Modulate 5-HT2A Receptors and Prevent in vivo Protein Toxicity in Transgenic Caenorhabditis elegans

Nordihydroguaiaretic Acid as a Novel Substrate and Inhibitor of Catechol O-Methyltransferase Modulates 4-Hydroxyestradiol-Induced Cyto- and Genotoxicity in MCF-7 Cells

Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches

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