Examinando por Autor "Yañez, Osvaldo"
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Ítem Biosystem analysis of the hypoxia inducible domain family member 2A: Implications in cancer biology(MDPI AG, 2020-02) Salazar, Celia; Yañez, Osvaldo; Elorza, Alvaro A.; Cortes, Natalie; García-Beltrán, Olimpo; Tiznado, William; Ruiz, Lina MaríaThe expression of HIGD2A is dependent on oxygen levels, glucose concentration, and cell cycle progression. This gene encodes for protein HIG2A, found in mitochondria and the nucleus, promoting cell survival in hypoxic conditions. The genomic location of HIGD2A is in chromosome 5q35.2, where several chromosomal abnormalities are related to numerous cancers. The analysis of high definition expression profiles of HIGD2A suggests a role for HIG2A in cancer biology. Accordingly, the research objective was to perform a molecular biosystem analysis of HIGD2A aiming to discover HIG2A implications in cancer biology. For this purpose, public databases such as SWISS-MODEL protein structure homology-modelling server, Catalogue of Somatic Mutations in Cancer (COSMIC), Gene Expression Omnibus (GEO), MethHC: a database of DNA methylation and gene expression in human cancer, and microRNA-target interactions database (miRTarBase) were accessed. We also evaluated, by using Real-Time Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR), the expression of Higd2a gene in healthy bone marrow-liver-spleen tissues of mice after quercetin (50 mg/kg) treatment. Thus, among the structural features of HIG2A protein that may participate in HIG2A translocation to the nucleus are an importin α-dependent nuclear localization signal (NLS), a motif of DNA binding residues and a probable SUMOylating residue. HIGD2A gene is not implicated in cancer via mutation. In addition, DNA methylation and mRNA expression of HIGD2A gene present significant alterations in several cancers; HIGD2A gene showed significant higher expression in Diffuse Large B-cell Lymphoma (DLBCL). Hypoxic tissues characterize the “bone marrow-liver-spleen” DLBCL type. The relative quantification, by using RT-qPCR, showed that Higd2a expression is higher in bone marrow than in the liver or spleen. In addition, it was observed that quercetin modulated the expression of Higd2a gene in mice. As an assembly factor of mitochondrial respirasomes, HIG2A might be unexpectedly involved in the change of cellular energetics happening in cancer. As a result, it is worth continuing to explore the role of HIGD2A in cancer biology. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.Ítem Cluster Assembled Silicon-Lithium Nanostructures: A Nanowire Confined Inside a Carbon Nanotube(Frontiers Media S.A., 2021-11) Orellana, Walter; Pino-Rios, Ricardo; Yañez, Osvaldo; Vásquez Espinal, Alejandro; Peccati, Francesca; Contreras García, Julia; Cardenas, Carlos; Tiznado, WilliamWe computationally explore an alternative to stabilize one-dimensional (1D) silicon-lithium nanowires (NWs). The Li12Si9 Zintl phase exhibits the NW (Formula presented.), combined with Y-shaped Si4 structures. Interestingly, this NW could be assembled from the stacking of the Li6Si5 aromatic cluster. The (Formula presented.) @CNT nanocomposite has been investigated with density functional theory (DFT), including molecular dynamics simulations and electronic structure calculations. We found that van der Waals interaction between Li’s and CNT’s walls is relevant for stabilizing this hybrid nanocomposite. This work suggests that nanostructured confinement (within CNTs) may be an alternative to stabilize this free NW, cleaning its properties regarding Li12Si9 solid phase, i.e., metallic character, concerning the perturbation provided by their environment in the Li12Si7 compound. Copyright © 2021 Orellana, Pino-Rios, Yañez, Vásquez-Espinal, Peccati, Contreras-García, Cardenas and Tiznado.Ítem Coumarin-chalcone hybrids as inhibitors of MAO-B: Biological activity and in silico studies(MDPI, 2021-04) Moya-Alvarado, Guillermo; Yañez, Osvaldo; Morales, Nicole; González-González, Angélica; Areche, Carlos; Núñez, Marco Tulio; Fierro, Angélica; García-Beltrán, OlimpoFourteen coumarin-derived compounds modified at the C3 carbon of coumarin with an α,β-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 neuro-protective 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 µM. 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. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Ítem Exploring the Potential Energy Surface of Medium-Sized Aromatic Polycyclic Systems with Embedded Planar Tetracoordinate Carbons: A Guided Approach(Multidisciplinary Digital Publishing Institute (MDPI), 2023-09) Inostroza, Diego; Leyva-Parra, Luis; Yañez, Osvaldo; Cooksy, Andrew L.; Thimmakondu, Venkatesan S.; Tiznado, WilliamThis study scrutinizes the complexities of designing and exploring the potential energy surfaces of systems containing more than twenty atoms with planar tetracoordinate carbons (ptCs). To tackle this issue, we utilized an established design rule to design a Naphtho [1,2-b:3,4-b′:5,6-b″:7,8-b′′′]tetrathiophene derivative computationally. This process began with substituting S atoms with CH− units, then replacing three sequential protons with two Si2+ units in the resultant polycyclic aromatic hydrocarbon polyanion. Despite not representing the global minimum, the newly designed Si8C22 system with four ptCs provided valuable insights into strategic design and potential energy surface exploration. Our results underscore the importance of employing adequate methodologies to confirm the stability of newly designed molecular structures containing planar hypercoordinate carbons. © 2023 by the authors.Ítem In Silico Study of Coumarins and Quinolines Derivatives as Potent Inhibitors of SARS-CoV-2 Main Protease(Frontiers Media S.A., 2021-02) Yañez, Osvaldo; Osorio, Manuel Isaías; Uriarte, Eugenio; Areche, Carlos; Tiznado, William; Pérez Donoso, José M.; García Beltrán, Olimpo; González Nilo, FernandoThe pandemic that started in Wuhan (China) in 2019 has caused a large number of deaths, and infected people around the world due to the absence of effective therapy against coronavirus 2 of the severe acute respiratory syndrome (SARS-CoV-2). Viral maturation requires the activity of the main viral protease (Mpro), so its inhibition stops the progress of the disease. To evaluate possible inhibitors, a computational model of the SARS-CoV-2 enzyme Mpro was constructed in complex with 26 synthetic ligands derived from coumarins and quinolines. Analysis of simulations of molecular dynamics and molecular docking of the models show a high affinity for the enzyme (∆Ebinding between −5.1 and 7.1 kcal mol−1). The six compounds with the highest affinity show Kd between 6.26 × 10–6 and 17.2 × 10–6, with binding affinity between −20 and −25 kcal mol−1, with ligand efficiency less than 0.3 associated with possible inhibitory candidates. In addition to the high affinity of these compounds for SARS-CoV-2 Mpro, low toxicity is expected considering the Lipinski, Veber and Pfizer rules. Therefore, this novel study provides candidate inhibitors that would allow experimental studies which can lead to the development of new treatments for SARS-CoV-2. © Copyright © 2021 Yañez, Osorio, Uriarte, Areche, Tiznado, Perez-Donoso, García-Beltrán and González-Nilo.Ítem Increased Absorption of Thyroxine in a Murine Model of Hypothyroidism Using Water/CO2 Nanobubbles(Multidisciplinary Digital Publishing Institute (MDPI), 2024-06) Opazo, Maria Cecilia; Yañez, Osvaldo; Márquez-Miranda, Valeria; Santos, Johana; Rojas, Maximiliano; Araya-Durán, Ingrid; Aguayo, Daniel; Leal, Matías; Duarte, Yorley; Kohanoff, Jorge; González-Nilo, Fernando D.Thyroxine (T4) is a drug extensively utilized for the treatment of hypothyroidism. However, the oral absorption of T4 presents certain limitations. This research investigates the efficacy of CO2 nanobubbles in water as a potential oral carrier for T4 administration to C57BL/6 hypothyroid mice. Following 18 h of fasting, the formulation was administered to the mice, demonstrating that the combination of CO2 nanobubbles and T4 enhanced the drug’s absorption in blood serum by approximately 40%. To comprehend this observation at a molecular level, we explored the interaction mechanism through which T4 engages with the CO2 nanobubbles, employing molecular simulations, semi-empirical quantum mechanics, and PMF calculations. Our simulations revealed a high affinity of T4 for the water–gas interface, driven by additive interactions between the hydrophobic region of T4 and the gas phase and electrostatic interactions of the polar groups of T4 with water at the water–gas interface. Concurrently, we observed that at the water–gas interface, the cluster of T4 formed in the water region disassembles, contributing to the drug’s bioavailability. Furthermore, we examined how the gas within the nanobubbles aids in facilitating the drug’s translocation through cell membranes. This research contributes to a deeper understanding of the role of CO2 nanobubbles in drug absorption and subsequent release into the bloodstream. The findings suggest that utilizing CO2 nanobubbles could enhance T4 bioavailability and cell permeability, leading to more efficient transport into cells. Additional research opens the possibility of employing lower concentrations of this class of drugs, thereby potentially reducing the associated side effects due to poor absorption.Ítem Kick-Fukui: A Fukui Function-Guided Method for Molecular Structure Prediction(American Chemical Society, 2021-08-23) Yañez, Osvaldo; Báez-Grez, Rodrigo; Inostroza, Diego; Pino-Rios, Ricardo; Rabanal-León, Walter A.; Contreras-García, Julia; Cardenas, Carlos; Tiznado, WilliamHere, we introduce a hybrid method, named Kick-Fukui, to explore the potential energy surface (PES) of clusters and molecules using the Coulombic integral between the Fukui functions in the first screening of the best individuals. In the process, small stable molecules or clusters whose combination has the stoichiometry of the explored species are used as assembly units. First, a small set of candidates has been selected from a large and stochastically generated (Kick) population according to the maximum value of the Coulombic integral between the Fukui functions of both fragments. Subsequently, these few candidates are optimized using a gradient method and density functional theory (DFT) calculations. The performance of the program has been evaluated to explore the PES of various systems, including atomic and molecular clusters. In most cases studied, the global minimum (GM) has been identified with a low computational cost. The strategy does not allow to identify the GM of some silicon clusters; however, it predicts local minima very close in energy to the GM that could be used as the initial population of evolutionary algorithms. ©Ítem Planar Elongated B12 Structure in M3B12 Clusters (M = Cu-Au)(MDPI, 2023-01) Solar-Encinas, José; Vásquez-Espinal, Alejandro; Leyva-Parra, Luis; Yañez, Osvaldo; Inostroza, Diego; Valenzuela, Maria Luisa; Orellana, Walter; Tiznado, WilliamHere, it is shown that the M3B12 (M = Cu-Au) clusters’ global minima consist of an elongated planar B12 fragment connected by an in-plane linear M3 fragment. This result is striking since this B12 planar structure is not favored in the bare cluster, nor when one or two metals are added. The minimum energy structures were revealed by screening the potential energy surface using genetic algorithms and density functional theory calculations. Chemical bonding analysis shows that the strong electrostatic interactions with the metal compensate for the high energy spent in the M3 and B12 fragment distortion. Furthermore, metals participate in the delocalized π-bonds, which infers an aromatic character to these species. © 2022 by the authors.Ítem Screening of the antileishmanial and antiplasmodial potential of synthetic 2-arylquinoline analogs(Nature Research, 2023-12) Espinosa‑Saez, Roger; Robledo, Sara M.; Pineda, Tatiana; Murillo, Javier; Zúñiga, César; Yañez, Osvaldo; Cantero‑López, Plinio; Saez‑Vega, Alex; Guzmán‑Teran, CamiloIn this study, six analogs of 2-arylquinoline were synthesized and evaluated for their in vitro and in vivo antiplasmodial and leishmanicidal activity. At a later stage, hemolytic activity and druggability were tested in vitro and in silico, respectively, observing as a result: firstly, compounds showed half-maximal effective concentration (EC50) values between 3.6 and 19.3 µM. Likewise, a treatment using the compounds 4a–f caused improvement in most of the treated hamsters and cured some of them. Regarding the antiplasmodial activity, the compounds showed moderate to high activity, although they did not show hemolytic activity. Furthermore, 4e and 4f compounds were not able to control P. berghei infection when administered to animal models. Molecular dynamic simulations, molecular docking and ligand binding affinity indicate good characteristics of the studied compounds, which are expected to be active. And lastly, the compounds are absorbable at the hematoencephalic barrier but not in the gastrointestinal tract. In summary, ADMET properties suggest that these molecules may be used as a safe treatment against Leishmania.Ítem Searching for double σ- And π-aromaticity in borazine derivatives(Royal Society of Chemistry, 2020-08) Pino-Rios, Ricardo; Vásquez-Espinal, Alejandro; Yañez, Osvaldo; Tiznado, WilliamInspired by the double-aromatic (σ and π) C6H3+, C6I62+, and C6(SePh)62+ ring-shaped compounds, herein we theoretically study their borazine derivative analogues. The systems studied are the cation and dications with formulas B3N3H3+, B3N3Br62+, B3N3I62+, B3N3(SeH)62+, and B3N3(TeH)62+. Our DFT calculations indicate that the ring-shaped planar structures of B3N3H3+, B3N3I62+, and B3N3(TeH)62+ are more stable in the singlet state, while those of B3N3Br62+ and B3N3(SeH)62+ prefer the triplet state. Besides, exploration of the potential energy surface shows that the ring-shaped structure is the putative global minimum only for B3N3I62+. According to chemical bonding analysis, B3N3H3+, B3N3I62+, and B3N3(TeH)62+ have σ and π delocalized bonds. The number of delocalized σ/π electrons is 2/6 for the first, and 10/6 for the second and third, similar to what their carbon analogs exhibit. Finally, the analysis of the magnetically induced current density allows B3N3H3+, B3N3I62+, and B3N3(TeH)62+ to be classified as strongly σ aromatic, and poorly π aromatic compounds. © The Royal Society of Chemistry.Ítem Searching for Systems with Planar Hexacoordinate Carbons(MDPI, 2023-03) Inostroza, Diego; Leyva-Parra, Luis; Yañez, Osvaldo; Solar-Encinas, José; Vásquez-Espinal, Alejandro; Valenzuela, Maria Luisa; Tiznado, WilliamHere, we present evidence that the D2h M2C50/2+ (M = Li-K, Be-Ca, Al-In, and Zn) species comprises planar hexacoordinate carbon (phC) structures that exhibit four covalent and two electrostatic interactions. These findings have been made possible using evolutionary methods for exploring the potential energy surface (AUTOMATON program) and the Interacting Quantum Atoms (IQA) methodology, which support the observed bonding interactions. It is worth noting, however, that these structures are not the global minimum. Nonetheless, incorporating two cyclopentadienyl anion ligands (Cp) into the CaC52+ system has enhanced the relative stability of the phC isomer. Moreover, cycloparaphenylene ([8]CPP) provides system protection and kinetic stability. These results indicate that using appropriate ligands presents a promising approach for expanding the chemistry of phC species. © 2023 by the authors.Ítem Theobroma cacao L. compounds: Theoretical study and molecular modeling as inhibitors of main SARS-CoV-2 protease(Elsevier Masson s.r.l., 2021-05) Yañez, Osvaldo; Osorio, Manuel Isaías; Areche, Carlos; Vásquez-Espinal, Alejandro; Bravo, Jessica; Sandoval-Aldana, Angélica; Perez-Donoso, José; González -Nilo, Fernando; Joao-Matos, Maria; Osorio, Edison; García Beltrán, Olimpo; Tiznado, WilliamCocoa beans contain antioxidant molecules with the potential to inhibit type 2 coronavirus (SARS-CoV-2), which causes a severe acute respiratory syndrome (COVID-19). In particular, protease. Therefore, using in silico tests, 30 molecules obtained from cocoa were evaluated. Using molecular docking and quantum mechanics calculations, the chemical properties and binding efficiency of each ligand was evaluated, which allowed the selection of 5 compounds of this series. The ability of amentoflavone, isorhoifolin, nicotiflorin, naringin and rutin to bind to the main viral protease was studied by means of free energy calculations and structural analysis performed from molecular dynamics simulations of the enzyme/inhibitor complex. Isorhoifolin and rutin stand out, presenting a more negative binding ΔG than the reference inhibitor N-[(5-methylisoxazol-3-yl)carbonyl]alanyl-L-valyl-N~1~-((1R,2Z)−4-(benzyloxy)−4-oxo-1-{[(3R)−2-oxopyrrolidin-3-yl]methyl}but-2-enyl)-L-leucinamide (N3). These results are consistent with high affinities of these molecules for the major SARS-CoV-2. The results presented in this paper are a solid starting point for future in vitro and in vivo experiments aiming to validate these molecules and /or test similar substances as inhibitors of SARS-CoV-2 protease. © 2021 The AuthorsÍtem Theoretical Study of the Antioxidant Activity of Quercetin Oxidation Products(Frontiers Media S.A., 2019-11) Vásquez-Espinal, Alejandro; Yañez, Osvaldo; Osorio, Edison; Areche, Carlos; García-Beltrán, Olimpo; Ruiz, Lina María; Cassels, Bruce K.; Tiznado, WilliamIt was recently shown that, when tested in cellular systems, quercetin oxidized products (Qox) have significantly better antioxidant activity than quercetin (Q) itself. The main Qox identified in the experiments are either 2,5,7,3′,4′-pentahydroxy-3,4-flavandione (Fl) or its tautomer, 2-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxy-3(2H)-benzofuranone (Bf). We have now performed a theoretical evaluation of different physicochemical properties using density functional theory (DFT) calculations on Q and its main Qox species. The most stable structures (for Q and Qox) were identified after a structural search on their potential energy surface. Since proton affinities (PAs) are much lower than the bond dissociation enthalpies (BDEs) of phenolic hydrogens, we consider that direct antioxidant activity in these species is mainly due to the sequential proton loss electron transfer (SPLET) mechanism. Moreover, our kinetic studies, according to transition state theory, show that Q is more favored by this mechanism. However, Qox have lower PAs than Q, suggesting that antioxidant activity by the SPLET mechanism should be a result of a balance between proclivity to transfer protons (which favors Qox) and the reaction kinetics of the conjugated base in the sequential electron transfer mechanism (which favors Q). Therefore, our results support the idea that Q is a better direct antioxidant than its oxidized derivatives due to its kinetically favored SPLET reactions. Moreover, our molecular docking calculations indicate a stabilizing interaction between either Q or Qox and the kelch-like ECH-associated protein-1 (Keap1), in the nuclear factor erythroid 2-related factor 2 (Nrf2)-binding site. This should favor the release of the Nrf2 factor, the master regulator of anti-oxidative responses, promoting the expression of the antioxidant responsive element (ARE)-dependent genes. Interestingly, the computed Keap1-metabolite interaction energy is most favored for the Bf compound, which in turn is the most stable oxidized tautomer, according to their computed energies. These results provide further support for the hypothesis that Qox species may be better indirect antioxidants than Q, reducing reactive oxygen species in animal cells by activating endogenous antioxidants. © Copyright © 2019 Vásquez-Espinal, Yañez, Osorio, Areche, García-Beltrán, Ruiz, Cassels and Tiznado.Ítem Theoretical Study of the Antioxidant Activity of Quercetin Oxidation Products(Frontiers Media S.A., 2019-11-27) Vásquez-Espinal, Alejandro; Yañez, Osvaldo; Osorio, Edison; Areche, Carlos; García-Beltrán, Olimpo; Ruiz, Lina María; Cassels, Bruce K.; Cassels B.K.; Tiznado, WilliamIt was recently shown that, when tested in cellular systems, quercetin oxidized products (Qox) have significantly better antioxidant activity than quercetin (Q) itself. The main Qox identified in the experiments are either 2,5,7,3′,4′-pentahydroxy-3,4-flavandione (Fl) or its tautomer, 2-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxy-3(2H)-benzofuranone (Bf). We have now performed a theoretical evaluation of different physicochemical properties using density functional theory (DFT) calculations on Q and its main Qox species. The most stable structures (for Q and Qox) were identified after a structural search on their potential energy surface. Since proton affinities (PAs) are much lower than the bond dissociation enthalpies (BDEs) of phenolic hydrogens, we consider that direct antioxidant activity in these species is mainly due to the sequential proton loss electron transfer (SPLET) mechanism. Moreover, our kinetic studies, according to transition state theory, show that Q is more favored by this mechanism. However, Qox have lower PAs than Q, suggesting that antioxidant activity by the SPLET mechanism should be a result of a balance between proclivity to transfer protons (which favors Qox) and the reaction kinetics of the conjugated base in the sequential electron transfer mechanism (which favors Q). Therefore, our results support the idea that Q is a better direct antioxidant than its oxidized derivatives due to its kinetically favored SPLET reactions. Moreover, our molecular docking calculations indicate a stabilizing interaction between either Q or Qox and the kelch-like ECH-associated protein-1 (Keap1), in the nuclear factor erythroid 2-related factor 2 (Nrf2)-binding site. This should favor the release of the Nrf2 factor, the master regulator of anti-oxidative responses, promoting the expression of the antioxidant responsive element (ARE)-dependent genes. Interestingly, the computed Keap1-metabolite interaction energy is most favored for the Bf compound, which in turn is the most stable oxidized tautomer, according to their computed energies. These results provide further support for the hypothesis that Qox species may be better indirect antioxidants than Q, reducing reactive oxygen species in animal cells by activating endogenous antioxidants.