Browsing by Author "Fierro, Angelica"
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- Item5-HT2 Receptor Subfamily and the Halogen Bond Promise(2021) Fierro, Angelica; Matthies, Douglas J.; Cassels, Bruce K.; Jaque, Pablo; Zapata-Torres, GeraldThe binding of C-4-halogenated 1-(4-X-2,5-dimethoxyphenyl)-2-aminopropane (DOX) serotonin agonist psychedelics at all three 5-HT2 receptor subtypes is up to two orders of magnitude stronger for X = Cl, Br, or I (but not F) than when C-4 bears a hydrogen atom and more than expected from their hydrophobicities. Our docking and molecular dynamics simulations agree with the fact that increasing the polarizability of halogens results in halogen-oxygen distances to specific backbone C=O groups, and C-X center dot center dot center dot O angles, in ranges expected for halogen bonds (XBs), which could contribute to the high affinities observed. Good linear correlations are found for each receptor type, indicating that the binding pocketl-igand affinity is enhanced as the XB interaction becomes stronger (i.e., I approximate to Br > Cl > F). It is also striking to note how the linear equations unveil that the receptor's response on the strength of the XB interaction is quite similar among 5-HT2A and 5-HT2C, whereas the 5-HT2B's sensitivity is less. The calculated dipole polarizabilities in the binding pocket of the receptors reflect the experimental affinity values, indicating that less-polarizable and harder binding sites are more prone to XB formation.
- ItemChanges in Protonation Sites of 3-Styryl Derivatives of 7-(dialkylamino)-aza-coumarin Dyes Induced by Cucurbit[7]uril(2022) Alcazar, Jackson J.; Marquez, Edgar; Garcia-Rio, Luis; Robles-Munoz, Agustin; Fierro, Angelica; Santos, Jose G.; Aliaga, Margarita E.The incorporation of a guest, with different basic sites, into an organized system (host), such as macrocycles, could stabilize, detect, or promote the formation of a certain protomer. In this context, this work aimed to study the influence of cucurbit[7]uril (CB7) on dyes such as 7-(dimethylamino)-aza-coumarins, which have more than one basic site along their molecular structure. For this, three 3-styryl derivatives of 7-(dialkylamino)-aza-coumarin dyes (SAC1-3) were synthesized and characterized by NMR, ESI-HRMS and IR. The spectral behaviour of the SACs in the absence and presence of CB7 was studied. The results showed large shifts in the UV-vis spectrum in acid medium: a hypsochromic shift of approximate to 5400 cm(-1) (SAC1-2) and approximate to 3500 cm(-1) (SAC3) in the absence of CB7 and a bathochromic shift of approximate to 4500 cm(-1) (SAC1-3) in the presence of CB7. The new absorptions at long and short wavelengths were assigned to the corresponding protomers by computational calculations at the density functional theory (DFT) level. Additionally, the binding mode was corroborated by molecular dynamics simulations. Findings revealed that in the presence of CB7 the heterocyclic nitrogen was preferably protonated instead of the dialkylamino group. Namely, CB7 induces a change in the protonation preference at the basic sites of the SACs, as consequence of the molecular recognition by the macrocycle.
- ItemCharacterization of a Novel Drosophila SERT Mutant: Insights on the Contribution of the Serotonin Neural System to Behaviors(2017) Hidalgo, Sergio; Molina-Mateo, Daniela; Escobedo, Pia; Zarate, Rafaella V.; Fritz, Elsa; Fierro, Angelica; Perez, Edwin G.; Iturriaga-Vasquez, Patricio; Reyes-Parada, Miguel; Varas, Rodrigo; Fuenzalida-Uribe, Nicolas; Campusano, Jorge M.A better comprehension on how different molecular components of the serotonergic system contribute to the adequate regulation of behaviors in animals is essential in the interpretation on how they are involved in neuropsychiatric and pathological disorders. It is possible to study these components in "simpler" animal models including the fly Drosophila melanogaster, given that most of the components of the serotonergic system are conserved between vertebrates and invertebrates. Here we decided to advance our understanding on how the serotonin plasma membrane transporter (SERT) contributes to serotonergic neurotransmission and behaviors in Drosophila. In doing this, we characterized for the first time a mutant for Drosophila SERT (dSERT) and additionally used a highly selective serotonin-releasing drug, 4-methylthioamphetamine (4-MTA), whose mechanism of action involves the SERT protein. Our results show that dSERT mutant animals exhibit an increased survival rate in stress conditions, increased basal motor behavior, and decreased levels in an anxiety-related parameter, centrophobism. We also show that 4-MTA increases the negative chemotaxis toward a strong aversive odorant, benzaldehyde. Our neurochemical data suggest that this effect is mediated by dSERT and depends on the 4-MTA-increased release of serotonin in the fly brain. Our in silico data support the idea that these effects are explained by specific interactions between 4-MTA and dSERT. In sum, our neurochemical, in silico, and behavioral analyses demonstrate the critical importance of the serotonergic system and particularly dSERT functioning in modulating several behaviors in Drosophila.
- ItemCollective and Coordinated Conformational Changes Determine Agonism or Antagonism at the Human Trace Amine-Associated Receptor 1(2023) Robles, Agustin I.; Dinamarca-Villarroel, Luis; Torres, Gonzalo E.; Fierro, AngelicaThe human trace amine-associated receptor (hTAAR1), a G protein-coupled receptor, has been postulated as a new target in the treatment of neuropsychiatric conditions. The mechanism associated with activation or inactivation by agonists or antagonists in hTAAR1 and other GPCRs has not yet been fully elucidated. In this study, we combined computational methods including homology modeling, docking, and molecular dynamic simulations to reveal novel conformational changes associated with agonist and antagonist interactions in hTAAR1. Our findings suggest a differential cascade of coordinated movements based on the presence of either an agonist or antagonist and primarily involving the second extracellular loop, transmembrane domain 5, and the third intracellular domains of hTAAR1. Our study provides an opportunity to predict the effects on new ligands with agonistic or antagonistic activity at hTAAR1 based on the reported conformational changes.
- ItemCoumarin-Chalcone Hybrids as Inhibitors of MAO-B: Biological Activity and In Silico Studies(2021) Moya-Alvarado, Guillermo; Yanez, Osvaldo; Morales, Nicole; Gonzalez-Gonzalez, Angelica; Areche, Carlos; Nunez, Marco Tulio; Fierro, Angelica; Garcia-Beltran, OlimpoFourteen coumarin-derived compounds modified at the C3 carbon of coumarin with an alpha,beta-unsaturated ketone were synthesized. These compounds may be designated as chalcocoumarins (3-cinnamoyl-2H-chromen-2-ones). Both chalcones and coumarins are recognized scaffolds in medicinal chemistry, showing diverse biological and pharmacological properties among which neuroprotective activities and multiple enzyme inhibition, including mitochondrial enzyme systems, stand out. The evaluation of monoamine oxidase B (MAO-B) inhibitors has aroused considerable interest as therapeutic agents for neurodegenerative diseases such as Parkinson's. Of the fourteen chalcocumarins evaluated here against MAO-B, ChC4 showed the strongest activity in vitro, with IC50 = 0.76 +/- 0.08 mu M. Computational docking, molecular dynamics and MM/GBSA studies, confirm that ChC4 binds very stably to the active rMAO-B site, explaining the experimental inhibition data.
- ItemCucurbit[7]uril as a Supramolecular Catalyst in Base-Catalyzed Reactions. Experimental and Theoretical Studies on Carbonate and Thiocarbonate Hydrolysis Reactions(2021) Fierro, Angelica; Garcia-Rio, Luis; Arancibia-Opazo, Sandra; Alcazar, Jackson J.; Santos, Jose G.; Aliaga, Margarita E.Cucurbit[7]uril (CB7) catalyzes the hydrolysis reaction of bis(4-nitrophenyl)carbonate (1) but inhibits that of bis(4-nitrophenyl)thiocarbonate (2). Two relevant CB7 effects are proposed, a base-catalyst mediated by the CB7 portal and an inhibitory role attributed to the lower interaction of the thiocarbonyl group with the solvent in the host cavity, respectively.
- ItemLinear relationship between emission quantum yield and Stokes shift in 3-styryl aza-coumarin based dyes in the presence of cyclodextrins(2023) Alcazar, Jackson J.; Garcia-Rio, Luis; Robles, Agustin I.; Dinamarca-Villarroel, Luis; Fierro, Angelica; Santos, Jose G.; Aliaga, Margarita E.The effect of the cyclodextrins inclusion on the Stokes shifts and emission quantum yield of three 3-styryl aza-coumarin dyes (SACs) was experimentally and theoretically studied. Preliminary results show a rela-tionship between the emission quantum yield and the calculated binding constants. Supramolecular inclusion was supported by changes in the fluorescence spectra, high-resolution mass spectrometry and molecular dynamics studies. 2,6-di-O-methyl-b-cyclodextrin (DM -b-CD) presented higher binding constants than b-cyclodextrin (b-CD), along with up to a 6-fold increase in emission quantum yield for the SACs. Additionally, a linear negative correlation was obtained between the Stokes shift and the emis-sion quantum yield. This linear and empirical relationship was explained by the action of a unique intramolecular rotation and charge transfer phenomenon in the dyes, which was modulated by cyclodex-trins, and supported by calculations based on density functional theory.(c) 2023 Elsevier B.V. All rights reserved.
- ItemSynthesis, docking and pharmacological evaluation of novel homo- and hetero-bis 3-piperazinylpropylindole derivatives at SERT and 5-HT1A receptor(2013) Pessoa-Mahana, Hernan; Gonzalez-Lira, Christian; Fierro, Angelica; Zapata-Torres, Gerald; David Pessoa-Mahana, C.; Ortiz-Severin, Javiera; Iturriaga-Vasquez, Patricio; Reyes-Parada, Miguel; Silva-Matus, Paul; Saitz-Barria, Claudio; Araya-Maturana, RamiroA series of 3-(3-(4-(3-(1H-indol-3-yl)propyl)piperazin-1-yl)propyl)-1H-indole derivatives (3a-d and 5a-f) as homo-and hetero-bis-ligands, were synthesized and evaluated for in vitro affinity at the serotonin transporter (SERT) and the 5-HT1A receptor. Compounds 5b and 5f showed nanomolar affinities for both targets. The experimental data were rationalized according to results obtained from docking experiments. These findings are in agreement with our proposal that bis-indole derivatives can bind both targets, and might serve as leads in the quest of ligands endowed with a dual mechanism of action. (C) 2013 Elsevier Ltd. All rights reserved.