Insercion de drogas en dendrimeros de PAMAM: analisis de las energias de interaccion

91 p.En esta Memoria de Título se diseño un sistema de análisis de cavidades internas en el dendrímeros de PAMAM-G5. Específicamente se calcularon las energías de interacción entre el dendrímero y las drogas Primidona y Fenobarbital, en estado neutro y cargado, utilizando las técnicas computacionales de dinámica molecular y Docking. La ejecución de los cálculos se realizó de manera distribuida, con el fin de analizar varias conformaciones de manera simultánea. El protocolo para obtener las distintas conformaciones de la interacción dendrímero-droga incluyó la creación de un espacio dentro del dendrímero con los programas TCLForces y NAMD, el uso de Autodock para insertar la droga dentro del dendrímero, y dinámica Molecular para obtener las energías de interacción con el script PairInteraction. Este último proceso se realizó de manera distribuida para la cantidad de generaciones que tiene el dendrímero. Las drogas que se utilizaron fueron parametrizadas con el campo de fuerza CHARMM, utilizando la herramienta Paratool, del software VMD. Para generar algunos de los parámetros de las drogas, ausentes en el campo de fuerza CHARMM, se realizaron cálculos de Química Cuántica con el programa Gaussian03. Después de obtener todos los sistemas droga-dendrímero, se obtuvieron las energías de Interacción entre el dendrímero y las drogas a través de Dinámica Molecular. Las energías de interacción no enlazantes, de tipo electrostática y de Van der Waals, se analizaron y compararon con datos experimentales obtenidos por otros laboratorios. Los resultados obtenidos muestran que las drogas cargadas tienen una mejor interacción, con las distintas regiones del dendrímero de PAMAM-G5, comparadas con las drogas neutras. Esto se explica debido a que las interacciones electrostáticas aumentan considerablemente gracias al nitrógeno libre del anillo barbitúrico en las drogas cargadas. En las drogas neutras, la contribución energética de las interacciones electrostáticas es similar a la energía de Van der Waals. Palabras Claves: Dendrímero, Energía de Interacción, Droga, Dinámica Molecular, Docking, Cavidades Internas/ ABSTRACT: In this written report an internal cavity in PAMAM-G5 dendrimers analysis system was designed. The interaction of the energies was calculated specifically, between the dendrimer and the Primidone and Phenobarbital drugs, in neutral and charged status, using computational tools such as molecular dynamics and Docking. The execution of the calculations was fulfilled in a distributed way with the aim of analyzing different conformations in a simultaneous way. The steps that were followed to obtain the different conformations of the dendrimer-drug interaction included the creation of a space within the dendrimer with TCLForces and NAMD, the use of Autodock to insert the drug in the dendrimer and molecular dynamics to obtain the energies of interaction with the PairInteraction script. The later process was made in distributed way for the quantities of generations that a dendrimer has. The drugs that were used were parameterized with the CHARMM forcefield, using Paratool, of VMD software. To generate some parameters of the drugs, missing in the CHARMM forcefield file, they were realized some Quantum Chemistry with the software Gaussian v03. After obtaining all the systems dendrimer-drug, they are obtained the interaction energies between the dendrimer and the drugs using molecular dynamics. The energies of interaction not bonding, electrostatic and Van der Waals type, they were analyzed and compare with experimental information obtained for another laboratories. The result obtained show the charged drugs have a better interaction, with the different regions of PAMAM-G5, that the neutral drugs. This explains due to the fact that the electrostatic interaction increase considerably thanks to the free nitrogen from the barbiturate ring in the charged drugs. In neutral drugs, energy contribution from electrostatic interaction is similar to Van der Waals energy. Key words: Dendrimers, Energy of interaction, Drugs, Molecular Dynamics, Docking, Internal Cavity

Estudio de las propiedades estructurales del proceso de hinchado y deshinchado del dendrimero PAMAM G4

67 p.Los dendrímeros son nanomoléculas poliméricas de estructura ramificada en forma de estrella. Esta estructura ramificada posibilita la formación de cavidades en su interior, lo que permite el encapsulamiento de drogas. El dendrímero PAMAM (poliamidoamina) posee grupos protonables que le otorgan propiedades específicas dependientes de pH. Estudios experimentales de SAXS y SANS muestran que los cambios conformacionales no son dependientes de pH en PAMAM. Nuestro estudio con dinámica molecular muestra que se produce un reordenamiento de los átomos debido a repulsiones electrostáticas provocadas por la protonación-desprotonación de sus grupos funcionales. Esto induciría la formación de cavidades internas que permiten la encapsulación de drogas. Este trabajo busca mostrar, utilizando métodos de dinámica molecular, los efectos de la variación de pH sobre la conformación molecular de PAMAM por variación de las cargas de grupos protonables de forma controlada durante la simulación, esta metodología no ha sido creada ni implementada en otras investigaciones. El análisis de propiedades como área de la superficie accesible al solvente, coeficientes de agregación y de función de distribución radial muestran que la variación de pH provoca un reordenamiento espacial de los grupos funcionales, asociado a la agrupación de dendrones en forma de ramilletes. Además estudios de radio de giro indican un cambio pequeño en el tamaño del dendrímero, resultados que sugieren que el proceso de captura de drogas al interior de PAMAM no se encuentra asociado a un proceso de hinchado y deshinchado, sino a procesos de reordenamiento de las cavidades al interior del dendrímero. Palabras claves: Dendrímero, PAMAM, protonación/ ABSTRACT: Dendrimers are polymeric nanomolecules branched in star shape. This branching structure makes possible the formation of cavities in its interior, which allows the encapsulation of drugs. The PAMAM dendrimer (polyamidoamine) have protonable groups that give specific properties dependent on pH. Previus SAXS and SANS experimental studies showed the pH undependence of PAMAM structural conformation changes. Our molecular dynamics experiments shows the same behavior with a rearrangement of atoms due to electrostatic repulsion caused by protonation-deprotonation process of the functional groups. This tesis work attempts to show, using molecular dynamics methods, the effects of pH variation on the molecular conformation of PAMAM by the alteration of the charges of protonables groups in a controlled manner during the simulation, this methodology this has not been created or implemented in other research. The analysis of properties such as surface area accessible to solvent, congregation coefficient and radial distribution function show the pH effect over the spatial rearrangement of the functional groups associated with the formation of group dendron shaped bouquets. Also the radius of gyration studies indicate a small change in the size of the dendrimer suggesting that the capture process within PAMAM drugs is not associated with a process of swelling and deflation, but to processes of reordering of the cavities within the dendrimer

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

Anales del III Congreso Internacional de Vivienda y Ciudad "Debate en torno a la nueva agenda urbana"

Acta de congresoEl III Congreso Internacional de Vivienda y Ciudad “Debates en torno a la NUEVa Agenda Urbana”, ha sido una apuesta de alto compromiso por acercar los debates centrales y urgentes que tensionan el pleno ejercicio del derecho a la ciudad. Para ello las instituciones organizadoras (INVIHAB –Instituto de Investigación de Vivienda y Hábitat y MGyDH-Maestría en Gestión y Desarrollo Habitacional-1), hemos convidado un espacio que se concretó con potencia en un debate transdisciplinario. Convocó a intelectuales de prestigio internacional, investigadores, académicos y gestores estatales, y en una metodología de innovación articuló las voces académicas con las de las organizaciones sociales y/o barriales en el Foro de las Organizaciones Sociales que tuvo su espacio propio para dar voz a quienes están trabajando en los desafíos para garantizar los derechos a la vivienda y los bienes urbanos en nuestras ciudades del Siglo XXI

A theoretical assessment of antioxidant capacity of flavonoids by means of local hyper–softness

A theoretical reactivity descriptor to estimate local reactivity on molecules was tested to assess the antioxidant capability of some flavonoids. It was validated by comparison with experimental precedents published already by Firuzi et al. (2005). The aforementioned reactivity index is called local hyper-softness (LHS). This parameter was applied on HO- substituent groups on the same set of flavonoids within each subclassification: flavones (apigenin and baicalein), flavonols (fisetin, galangin, 3–OH flavone, kaempferol, myricetin, and quercetin), flavanones (hesperetin, naringenin, taxifolin) and isoflavones (daidzein and genistein). Experimental values of both techniques, ferric reducing antioxidant power (FRAP) and anodic oxidation potential (Eap) were retrieved from Firuzi et al. (2005) with the purpose of validating the calculated LHS values. Excepting myricetin, the LHS values of all these compounds matched in a similar order relationship experimentally obtained by means of Eap and FRAP from Firuzi et al. (2005). Our results revealed that LHS is a suitable theoretical parameter to get an insight concerning to the antioxidant capacity of these compounds, in particular, LHS allows explaining experimentally obtained values of FRAP along with Eap values in terms of reactivity of HO- substituent groups belonging these molecules theoretically computed without including experimental parametes. Keywords: Flavonoids, Antioxidant capacity, Ferric reducing antioxidant power, Anodic oxidation potential, Local hypersoftnes

Phenolic Profile and Cholinesterase Inhibitory Properties of Three Chilean Altiplano Plants: <i>Clinopodium gilliesii</i> (Benth.) Kuntze [Lamiaceae], <i>Mutisia acuminata</i> Ruiz & Pav. var. hirsuta (Meyen) Cabrera, and <i>Tagetes multiflora</i> (Kunth) [Asteraceae]

This research aimed to identify the phenolic profile and composition of the aerial parts of three native species used in traditional medicine in the Andean Altiplano of northern Chile: Clinopodium gilliesii (Benth.) Kuntze [Lamiaceae] (commonly known as Muña-Muña), Mutisia acuminata Ruiz & Pav. var. hirsuta (Meyen) Cabrera [Asteraceae] (commonly known as Chinchircoma), and Tagetes multiflora (Kunth), [Asteraceae] (commonly known as Gracilis), as well as to evaluate their potential inhibitory effects against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Polyphenolic enriched-extracts (PEEs) of the species were prepared and analyzed and the main components were quantified using HPLC-DAD. In total, 30 phenolic compounds were identified and quantified in all species, including simple phenolics, hydroxycinnamic acids, flavan-3-ols (monomers and polymers), flavanones, and flavonols. In addition, other main phenolics from the extracts were tentatively identified by ESI-MS-MS high-resolution analysis. T. multiflora extract showed the greatest anti-AChE and BChE activity in comparison with C. gilliesii and M. acuminata extracts, being the anti-AChE and BChE activity weak in all extracts in comparison to galantamine control. To comprise to better understand the interactions between cholinesterase enzymes and the main phenolics identified in T. multiflora, molecular docking analysis was conducted