Potential colchicine binding site inhibitors unraveled by virtual screening, molecular dynamics and MM/PBSA.

Microtubules have been widely studied in recent decades as an important pharmacological target for the treatment of cancer especially due to its key role in the mitosis process. Among the constituents of the microtubules, αß-tubulin dimers stand out in view of their four distinct interaction sites, including the so-called colchicine binding site (CBS) - a promising target for the development of new tubulin modulators. When compared to other tubulin sites, targeting the CBS is advantageous because this site is able to host ligands with lower molecular volume and lipophilicity, thus reducing the chances of entailing the phenomenon of multiple drug resistance (MDR) - one of the main reasons of failure in chemotherapy. However, colchicine, the first ligand ever discovered with affinity towards the CBS, despite modulating the action of microtubules, has shown toxicity in clinical studies. Therefore, in order to expand the known chemical space of scaffolds capable of interacting with CBS and to design non-toxic colchicine binding site inhibitors, we conducted a robust virtual screening pipeline. This has been rigorously validated and consisted of ligand- and structure-based methodologies, which allowed us to select four promising CBS inhibitors called tubLCQF1-4. These four compounds were also evaluated with long trajectories molecular dynamics simulations and respective results were used for the theoretical determination of the free energy released in the formation of the complexes, using the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) methodology.

An Antioxidant Potential, Quantum-Chemical and Molecular Docking Study of the Major Chemical Constituents Present in the Leaves of Curatella americana Linn.

Reactive oxygen species (ROS) are continuously generated in the normal biological systems, primarily by enzymes as xanthine oxidase (XO). The inappropriate scavenging or inhibition of ROS has been considered to be linked with aging, inflammatory disorders, and chronic diseases. Therefore, many plants and their products have been investigated as natural antioxidants for their potential use in preventive medicine. The leaves and bark extracts of Curatella americana Linn. were described in scientific research as anti-inflammatory, vasodilator, anti-ulcerogenic, and hypolipidemic effects. So, the aim of this study was to evaluate the antioxidant potentials of leaf hydroalcoholic extract from C. americana (HECA) through the scavenging DPPH assay and their main chemical constituents, evaluated by the following quantum chemical approaches (DFT B3LYP/6-31G**): Maps of Molecular Electrostatic Potential (MEP), Frontier Orbital's (HOMO and LUMO) followed by multivariate analysis and molecular docking simulations with the xanthine oxidase enzyme. The hydroalcoholic extract showed significant antioxidant activity by free radical scavenging probably due to the great presence of flavonoids, which were grouped in the PCA and HCA analysis with the standard gallic acid. In the molecular docking study, the compounds studied presented the binding free energy (ΔG) values close each other, due to the similar interactions with amino acids residues at the activity site. The descriptors Gap and softness were important to characterize the molecules with antioxidant potential by capturing oxygen radicals.

GRIND2-based 3D-QSAR and prediction of activity spectra for symmetrical bis-pyridinium salts with promastigote antileishmanial activity.

Leishmaniasis is a major group of neglected tropical diseases caused by the protozoan parasite Leishmania. About 12 million people are affected in 98 countries and 350 million people worldwide are at risk of infection. Current leishmaniasis treatments rely on a relatively small arsenal of drugs, including amphotericin B, pentamidine and others, which in general have some type of inconvenience. Recently, we have synthesized antileishmanial bis-pyridinium derivatives and symmetrical bis-pyridinium cyclophanes. These compounds are considered structural analogues of pentamidine, where the amidino moiety, protonated at physiological pH, is replaced by a positively charged nitrogen atom as a pyridinium ring. In this work, a statistically significant GRIND2-based 3D-QSAR model was built and biological activity predictions were in silico carried out allowing rationalization of the different activities recently obtained against Leishmania donovani (in L. donovani promastigotes) for a data set of 19 bis-pyridinium compounds. We will emphasize the most important structural requirements to improve the biological activity and probable interactions with the biological receptor as a guide for lead and prototype optimization. In addition, since no information about the actual biological target for this series of active compounds is provided, we have used Prediction of Activity Spectra for Biologically Active Substances to propose our compounds as potential nicotinic α6ß3ß4α5 receptor antagonists. This proposal is reinforced by the high structural similarity observed between our compounds and several anthelmintic drugs in current clinical use, which have the same drug action mechanism here predicted. Such new findings would be confirmed with further and additional experimental assays.

4-amino bis-pyridinium derivatives as novel antileishmanial agents.

The antileishmanial activity of a series of bis-pyridinium derivatives that are analogues of pentamidine have been investigated, and all compounds assayed were found to display activity against promastigotes and intracellular amastigotes of Leishmania donovani and Leishmania major, with 50% effective concentrations (EC50s) lower than 1 µM in most cases. The majority of compounds showed similar behavior in both Leishmania species, being slightly more active against L. major amastigotes. However, compound VGP-106 {1,1'-(biphenyl-4,4'-diylmethylene)bis[4-(4-bromo-N-methylanilino)pyridinium] dibromide} exhibited significantly higher activity against L. donovani amastigotes (EC50, 0.86 ± 0.46 µM) with a lower toxicity in THP-1 cells (EC50, 206.54 ± 9.89 µM). As such, VGP-106 was chosen as a representative compound to further elucidate the mode of action of this family of inhibitors in promastigote forms of L. donovani. We have determined that uptake of VGP-106 in Leishmania is a temperature-independent process, suggesting that the compound crosses the parasite membrane by diffusion. Transmission electron microscopy analysis showed a severe mitochondrial swelling in parasites treated with compound VGP-106, which induces hyperpolarization of the mitochondrial membrane potential and a significant decrease of intracellular free ATP levels due to the inhibition of ATP synthesis. Additionally, we have confirmed that VGP-106 induces mitochondrial ROS production and an increase in intracellular Ca(2+) levels. All these molecular events can activate the apoptotic process in Leishmania; however, propidium iodide assays gave no indication of DNA fragmentation. These results underline the potency of compound VGP-106, which may represent a new avenue for the development of novel antileishmanial compounds.

Sé tú el cambio que quieras ver en la Universidad / You must be the change you want to see in the University

Se discutirán las dos primeras misiones de la Universidad, tales como la docencia y la investigación.Además, las relaciones inter-personales son fundamentales en todo grupo humano y se abordará elpapel del liderazgo en el grupo de investigación de acuerdo con las modernas tendencias del mundoempresarial.La Universidad española se encuentra en una situación excesivamente alejada de la realidad social yeconómica en la que vivimos. El enfoque del Espacio Europeo de Enseñanza Superior puede subsanarestas deficiencias, pero la adaptación conlleva, en mayor o menor grado, una transformación delmodelo educativo actual. Lo que no está claro es que las universidades españolas hayan alcanzado oestén en vías de alcanzar plenamente la nueva configuración de la Declaración de Bolonia. Más bienestán en una situación transitoria, ambigua, en la que permanecen rasgos anteriores con los nuevos.Con respecto al papel carismático del líder dentro de un grupo, merecen ser destacados aspectos talescomo la motivación, delegación y resolución de conflictos, entre los muchos valores que debenadornarlo.La Universidad de Granada es una institución muy grande. El secreto para que funcione esta macroestructuraes que cada uno de sus componentes, dentro de su status, se identifique con sus principios yse comprometa a cumplir con sus funciones, tanto particulares como generales. El secreto del éxito es la ilusión, trabajo y generosidad. Es así y sólo así, cuando el trabajo y la colaboración comprometidade todos sus miembros, dará lugar a una Universidad mejor(AU)

Teaching and research, two missions of the University, will be discussed herein. Moreover, the interpersonalrelationships are fundamental in all human groups and the role of the leadership in theresearch group will be tackled according to the modern tendencies of the business world.The Spanish University has been too distanced from the social and economical reality. The approachof the European higher education system may overcome all these shortcomings, but the adaptationmay lead, to a greater or a lesser degree, to a transformation of the present education system. It is notclear that the Spanish universities have reached or are now being fully reaching the new configurationof the Bologna Declaration. They are rather in a temporary ambiguous situation, in which someprevious features remain with the new ones.In relation to the charismatic role of the leader within a group, aspects such as motivation, delegationof functions and resolution of conflicts warrant the greatest attention among the many values that mustenhance it.The University of Granada is a vast institution. The secret for this macro-structure to work is that itscomponents, each within its own status, be identified with its principles and be committed toobserving its functions, both particular and general. The secret of the success is illusion, work andgenerosity. Only thus, when work and collaboration implicating all its members is a better Universitypossible(AU)