Browsing by Author "Yanez, Osvaldo"

Now showing 1 - 7 of 7
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    Colloidal nanomedicines with prolonged release of chloroquine based on interactions with aromatic polymers after mixing two liquids: from in silico simulation of nanoparticle formation to efficient in-bench scale up
    (2024) Villamizar-Sarmiento, Maria Gabriela; Yanez, Osvaldo; Flores, Mario E.; Alvarez-Acevedo, Gonzalo; Gonzalez-Nilo, Fernando; Guerrero, Juan; Moreno-Villoslada, Ignacio; Oyarzun-Ampuero, Felipe A.
    Nanomedicines containing the aromatic drug chloroquine and the polymer poly(sodium 4-styrenesulfonate) have been theoretically designed and experimentally synthesized following the simple mixture of two aqueous solutions containing the drug and the polymer, respectively. Theoretical calculations show higher binding energy between both the aromatic polymer and chloroquine, and a higher tendency to release water from their hydration spheres, as compared to the binding between the drug and the aliphatic polymer poly(sodium vinyl sulfonate). MD simulations show the spontaneous formation of stable structures of 10 nm of average diameter, even combining short polymer chains, highly diluted reactants, and short reaction time (in the range of mu s). Rapid mixture of the liquids in a stopped flow equipment shows nanoparticle formation in the range of tenths of seconds. Equilibration studies in the range of minutes evidence spheroidal nanoparticles with almost quantitative association efficiency, 48.6 % of drug loading, size of 170 - 410 nm, low polydispersity (PdI = 0.25 - 0.47), and negative zeta potential (-18 - -45 mV). They provide drug release for 30 days, and are stable to NaCl exposure, pH gradient, several temperature values, and long-term storage. Furthermore, we demonstrate scaling up of the nanomedicine production upon increasing the reaction volume. Our studies demonstrate that these highly loaded drug nanoparticles are based on the occurrence of site -specific short-range interactions between the drug and the aromatic excipient such as pi-stacking. In the absence of the aromatic group in the polymer, weak interactions and unstable formulations are evidenced, both theoretically and experimentally. The combination of the selected theoretical and experimental tools could promote the efficient production of drug / polyelectrolyte formulations with therapeutical applications. The chosen components could be considered as potential medicines or as model components to design, develop, characterize, and scale up medicines comprising other combinations of drugs and polymers.
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    Coumarin-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, Olimpo
    Fourteen 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.
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    Discovery of New 2-Phenylamino-3-acyl-1,4-naphthoquinones as Inhibitors of Cancer Cells Proliferation: Searching for Intra-Cellular Targets Playing a Role in Cancer Cells Survival
    (2023) Benites, Julio; Valderrama, Jaime A.; Contreras, Alvaro; Enriquez, Cinthya; Pino-Rios, Ricardo; Yanez, Osvaldo; Calderon, Pedro Buc
    A series of 2-phenylamino-3-acyl-1,4-naphtoquinones were evaluated regarding their in vitro antiproliferative activities using DU-145, MCF-7 and T24 cancer cells. Such activities were discussed in terms of molecular descriptors such as half-wave potentials, hydrophobicity and molar refractivity. Compounds 4 and 11 displayed the highest antiproliferative activity against the three cancer cells and were therefore further investigated. The in silico prediction of drug likeness, using pkCSM and SwissADME explorer online, shows that compound 11 is a suitable lead molecule to be developed. Moreover, the expressions of key genes were studied in DU-145 cancer cells. They include genes involved in apoptosis (Bcl-2), tumor metabolism regulation (mTOR), redox homeostasis (GSR), cell cycle regulation (CDC25A), cell cycle progression (TP53), epigenetic (HDAC4), cell-cell communication (CCN2) and inflammatory pathways (TNF). Compound 11 displays an interesting profile because among these genes, mTOR was significantly less expressed as compared to control conditions. Molecular docking shows that compound 11 has good affinity with mTOR, unraveling a potential inhibitory effect on this protein. Due to the key role of mTOR on tumor metabolism, we suggest that impaired DU-145 cells proliferation by compound 11 is caused by a reduced mTOR expression (less mTOR protein) and inhibitory activity on mTOR protein.
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    Exploring the adsorption of five emerging pollutants on activated carbon: A theoretical approach
    (2024) Gonzalez-Rodriguez, Lisdelys; Yanez, Osvaldo; Mena-Ulecia, Karel; Hidalgo-Rosa, Yoan; Garcia-Carmona, Ximena; Ulloa-Tesser, Claudia
    The identification and management of contaminants of emerging concern (CECs) in water systems is crucial for protecting public and environmental health. This paper reports a theoretical approach to studying the adsorption of five CECs: Atrazine (ATZ), Caffeine (CAF), Carbamazepine (CBZ), Sulfamethoxazole (SMX), and Ibuprofen (IBU) - onto Activated Carbon (AC). A set of computational methods, including electrostatic molecular potential maps, conceptual density functional theory, Fukui functions, thermodynamic analysis, and tight-binding molecular dynamics simulations, were employed to analyze the electronic/energetic interactions and mechanisms involved in the adsorption of CECs on AC. The theoretical methodology offered valuable predictions on reactivity sites, stability, and binding mechanisms. Results showed that adsorption primarily occurred through non-covalent interactions like pi-pi electron donor-acceptor interactions, van der Waals forces, and hydrophobic interactions. Thermodynamic properties suggested the adsorption process was spontaneous and exothermic. However, for the AC/SMX system, the Gibbs free energy reveals that adsorption may be unfavorably compared to the other study systems. Molecular dynamics simulations validated the kinetic stability in the following order CAF (0.13 & Aring;)>CBZ (0.23 & Aring;)>ATZ (0.75 & Aring;)> IBU (1.28 & Aring;)>SMX (1.54 & Aring;). This exploratory theoretical study provides a deep understanding of the interactions between AC and five CECs, aiding in the rational design and optimization of AC-based treatment systems for environmental and industrial applications.
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    Investigating micelle formation in systems with benzethonium chloride and n-lauroyl sarcosine sodium salt: The impact of thermal effects and ethyl lactate concentration using volumetric, statistical, acoustic, and molecular dynamic methods
    (2024) Fatma, Ishrat; Cantero-Lopez, Plinio; Sharma, Vivek; Yanez, Osvaldo; Correa, Cristian; Sanchez, Julio; Thakur, Ramesh Chand; Kumar, Ashish
    Surface active agents (SAAs) are versatile molecules that possess the ability to serve as multifunctional ingredients in a wide range of consumer products across various industrial sectors. These molecules can act as wetting and dispersion agents, emulsifiers, foaming and anti-foaming agents, lubricants, and more. The objective of this study was to evaluate the effect of temperature, and ethyl lactate concentration on micelle formation in systems containing benzethonium chloride (BC) and N-lauroyl sarcosine sodium salt (NLSS). The experimental measurements were conducted at three equidistant temperatures i.e., 298.15 K to 318.15 K and pressure, P=0.1 =0.1 MPa. Several volumetric as well as compressibility parameters including apparent molar properties ( V phi , K phi , S ), partial molar properties (V degrees phi , V degrees phi , K degrees phi, S ), transport properties ( Delta tr V degrees phi , Delta tr K degrees phi, S ), hydration number, etc. have been evaluated. A Bayesian two-factor design with uninformative priors was used to analyze the values of V degrees phi , and K degrees phi,S. S . It was possible to determine that the temperature factors, and the ethyl lactate (EL) addition significantly influence the results for V degrees phi while for K degrees phi, S it is not appreciable at 5and 10% in EL concentration when BC and NLSS systems is compared. The simulations of the micellization process show the impact of temperature, particularly in the presence of ethyl lactate, is evident in the structural and dynamic changes observed in the micelles. Specifically, as the temperature rises from 298.15 K to 318.15 K, the self-assembly process becomes more spontaneous and accelerated, leading to larger and more spherical micelles. These alterations in micelle size, shape, and orientation enhance their capacity to effectively solubilize hydrophobic substances. The computational simulations demonstrated that BC molecules exhibit spontaneous aggregation at the interface of polarnonpolar systems, resulting in the formation of a monolayer. In this monolayer, the heads of the molecules are oriented towards the polar phase, while the hydrophobic tails are in the nonpolar phase. Similarly, the NLSS system exhibits a continuous and gradual process of self-organization over a period of 120 ns, where NLSS molecules naturally come together to create a single layer arrangement at the zigzag-shaped boundary.
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    Nature of host-guest interaction of cyclic alcohols in β-Cyclodextrin: A molecular view of its structural features
    (2025) Cantero-Lopez, Plinio; Sanchez, Julio; Meza, Manuel S. Paez; Garcia-Negrete, C. A.; Bustos, Daniel; Yanez, Osvaldo
    Host- guest complexes are commonly found in several disciplines such as biochemistry, cosmetics, food, pharmaceuticals, and the environment. Studying the relationships between host and guest is essential in this context to understand their physicochemical behavior. This study aimed to examine the intermolecular interactions of cyclic alcohols within n- cyclodextrin (n- CD). The experimental spectroscopic results demonstrated the formation of the studied complexes. In this work, two orientations were used: orientation A (hydroxyl group toward the primary hydroxyl of n- CD) and orientation B (hydroxyl group toward the secondary hydroxyl of n- CD). The results indicate that regardless of the orientation used, the profile energy is thermodynamically favorable. However, there are differences in terms of greater or less stability in terms of the thermodynamic parameters studied. Physicochemical properties demonstrate that the host-guest complex forms spontaneously, and exothermic mode. The interaction between cyclic alcohols and n- CD in orientation A promotes a more pronounced deformation of the secondary edge of n- CD. Moreover, the arrangement of molecules demonstrates that intramolecular hydrogen bonds are less stable between the glycosidic units of n- CD. This arrangement may help or hinder the development of intermolecular hydrogen bonds.
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    Steady State Kinetics for Enzymes with Multiple Binding Sites Upstream of the Catalytic Site
    (2023) Osorio, Manuel I.; Petrache, Mircea; Salinas, Dino G.; Valenzuela-Ibaceta, Felipe; Gonzalez-Nilo, Fernando; Tiznado, William; Perez-Donoso, Jose M.; Bravo, Denisse; Yanez, Osvaldo
    The Michaelis-Menten mechanism, which describes the binding of a substrate to an enzyme, is a simplification of the process on a molecular scale. A more detailed model should include the binding of the substrate to precatalytic binding sites (PCBSs) prior to the transition to the catalytic site. Our work shows that the incorporation of PCBSs, in steady-state conditions, generates a Michaelis-Menten-type expression, in which the kinetic parameters KM and Vmax adopt more complex expressions than in the model without PCBSs. The equations governing reaction kinetics can be seen as generalized symmetries, relative to time translation actions over the state space of the underlying chemical system. The study of their structure and defining parameters can be interpreted as looking for invariants associated with these time evolution actions. The expression of KM decreases as the number of PCBSs increases, while Vmax reaches a minimum when the first PCBSs are incorporated into the model. To evaluate the trend of the dynamic behavior of the system, numerical simulations were performed based on schemes with different numbers of PCBSs and six conditions of kinetic constants. From these simulations, with equal kinetic constants for the formation of the Substrate/PCBS complex, it is observed that KM and Vmax are lower than those obtained with the Michaelis-Menten model. For the model with PCBSs, the Vmax reaches a minimum at one PCBS and that value is maintained for all of the systems evaluated. Since KM decreases with the number of PCBSs, the catalytic efficiency increases for enzymes fitting this model. All of these observations are consistent with the general equation obtained. This study allows us to explain, on the basis of the PCBS to KM and Vmax ratios, the effect on enzyme parameters due to mutations far from the catalytic site, at sites involved in the first enzyme/substrate interaction. In addition, it incorporates a new mechanism of enzyme activity regulation that could be fundamental to search for new activity-modulating sites or for the design of mutants with modified enzyme parameters.