New applications for known drugs: Human glycogen synthase kinase 3 inhibitors as modulators of Aspergillus fumigatus growth [Postprint]

Invasive aspergillosis (IA) is one of the most severe forms of fungi infection. IA disease is mainly due to Aspergillus fumigatus, an air-borne opportunistic pathogen. Mortality rate caused by IA is still very high (50-95%), because of difficulty in early diagnostics and reduced antifungal treatment options, thus new and efficient drugs are necessary. The aim of this work is, using Aspergillus nidulans as non-pathogen model, to develop efficient drugs to treat IA. The recent discovered role of glycogen synthase kinase-3 homologue, GskA, in A. fumigatus human infection and our previous experience on human GSK-3 inhibitors focus our attention on this kinase as a target for the development of antifungal drugs. With the aim to identify effective inhibitors of colonial growth of A. fumigatus we use A. nidulans as an accurate model for in vivo and in silico studies. Several well-known human GSK-3β inhibitors were tested for inhibition of A. nidulans colony growth. Computational tools as docking studies and binding site prediction was used to explain the different biological profile of the tested inhibitors. Three of the five tested hGSK3β inhibitors are able to reduce completely the colonial growth by covalent bind to the enzyme. Therefore these compounds may be useful in different applications to eradicate IA.SAF2012-37979-C03-01 to A.M; BFU2012-33142 to E.A.EN

La importancia de los intereses académicos en la política científica y tecnológica catalana

Publicado en: 'Papers: Revista de Sociología', 70: 11-40, 2003Este artículo describe la emergencia y orientación de las políticas de I+D e innovación en Cataluña. Se analizan cuáles son los factores más influyentes en la orientación de estas políticas y, en definitiva, en las opciones políticas que se toman. La política de ciencia y tecnología desarrollada por el gobierno regional catalán desde principios de los años ochenta ha sido una política en la que, a pesar de las preferencias manifestadas en el discurso político, ha predominado un modelo de política académico sobre el de orientación empresarial. Asimismo, en términos organizativos e institucionales, en la Administración autonómica, la política científica ha estado separada y diferenciada de la política tecnológica a pesar del diseño inicial de instituciones interdepartamentales. La principal razón de que la política de I+D catalana no siguiera un modelo más industrial, ligado al mundo empresarial, fue la presión que ejercieron las universidades catalanas para que, tanto el diseño institucional como el contenido de la política se adaptara a sus necesidades. La trayectoria académica previa de los gestores también contribuyó a la reorientación de las preferencias políticas. A pesar de la importancia de las empresas catalanas en la I+D, éstas no se movilizaron ni presionaron a los gobiernos suficientemente. Analíticamente, este caso ilustra cómo la sola creación política de instituciones no garantiza la realización de las preferencias políticas. También pone de manifiesto cómo el horizonte temporal de la toma de decisiones gubernamental tiene un efecto en las expectativas de los actores, que desarrollan procesos de aprendizaje a partir de las experiencias en arenas políticas similares a otros niveles. Por último, destaca la importancia del poder en las instituciones de gestión en este tipo de política distributiva.Peer reviewe

La importancia de los intereses académicos en la política científica y tecnológica catalana

Publicado en: 'Papers: Revista de Sociología', 70: 11-40, 2003Este artículo describe la emergencia y orientación de las políticas de I+D e innovación en Cataluña. Se analizan cuáles son los factores más influyentes en la orientación de estas políticas y, en definitiva, en las opciones políticas que se toman. La política de ciencia y tecnología desarrollada por el gobierno regional catalán desde principios de los años ochenta ha sido una política en la que, a pesar de las preferencias manifestadas en el discurso político, ha predominado un modelo de política académico sobre el de orientación empresarial. Asimismo, en términos organizativos e institucionales, en la Administración autonómica, la política científica ha estado separada y diferenciada de la política tecnológica a pesar del diseño inicial de instituciones interdepartamentales. La principal razón de que la política de I+D catalana no siguiera un modelo más industrial, ligado al mundo empresarial, fue la presión que ejercieron las universidades catalanas para que, tanto el diseño institucional como el contenido de la política se adaptara a sus necesidades. La trayectoria académica previa de los gestores también contribuyó a la reorientación de las preferencias políticas. A pesar de la importancia de las empresas catalanas en la I+D, éstas no se movilizaron ni presionaron a los gobiernos suficientemente. Analíticamente, este caso ilustra cómo la sola creación política de instituciones no garantiza la realización de las preferencias políticas. También pone de manifiesto cómo el horizonte temporal de la toma de decisiones gubernamental tiene un efecto en las expectativas de los actores, que desarrollan procesos de aprendizaje a partir de las experiencias en arenas políticas similares a otros niveles. Por último, destaca la importancia del poder en las instituciones de gestión en este tipo de política distributiva.Este trabajo se ha realizado gracias a la financiación del Programa Marco de I+D, del PRICIT de la Comunidad de Madrid y del III Plan Nacional de I+D de la CICYT (SEC 1999-0829-C02-01).Peer reviewe

Hybridizing Feature Selection and Feature Learning Approaches in QSAR Modeling for Drug Discovery

Quantitative structure–activity relationship modeling using machine learning techniques constitutes a complex computational problem, where the identification of the most informative molecular descriptors for predicting a specific target property plays a critical role. Two main general approaches can be used for this modeling procedure: feature selection and feature learning. In this paper, a performance comparative study of two state-of-art methods related to these two approaches is carried out. In particular, regression and classification models for three different issues are inferred using both methods under different experimental scenarios: two drug-like properties, such as blood-brain-barrier and human intestinal absorption, and enantiomeric excess, as a measurement of purity used for chiral substances. Beyond the contrastive analysis of feature selection and feature learning methods as competitive approaches, the hybridization of these strategies is also evaluated based on previous results obtained in material sciences. From the experimental results, it can be concluded that there is not a clear winner between both approaches because the performance depends on the characteristics of the compound databases used for modeling. Nevertheless, in several cases, it was observed that the accuracy of the models can be improved by combining both approaches when the molecular descriptor sets provided by feature selection and feature learning contain complementary information.Fil: Ponzoni, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Ciencias e Ingeniería de la Computación. Universidad Nacional del Sur. Departamento de Ciencias e Ingeniería de la Computación. Instituto de Ciencias e Ingeniería de la Computación; ArgentinaFil: Sebastián Pérez, Víctor. Consejo Superior de Investigaciones Científicas. Centro de Investigaciones Biológicas; EspañaFil: Requena Triguero, Carlos. Consejo Superior de Investigaciones Científicas. Centro de Investigaciones Biológicas; EspañaFil: Roca, Carlos. Consejo Superior de Investigaciones Científicas. Centro de Investigaciones Biológicas; EspañaFil: Martínez, María Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Ciencias e Ingeniería de la Computación. Universidad Nacional del Sur. Departamento de Ciencias e Ingeniería de la Computación. Instituto de Ciencias e Ingeniería de la Computación; ArgentinaFil: Cravero, Fiorella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Planta Piloto de Ingeniería Química. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; ArgentinaFil: Diaz, Monica Fatima. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Planta Piloto de Ingeniería Química. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; ArgentinaFil: Páez, Juan A.. Consejo Superior de Investigaciones Científicas. Instituto de Química Médica; EspañaFil: Gómez Arrayás, Ramón. Universidad Autónoma de Madrid; EspañaFil: Adrio, Javier. Universidad Autónoma de Madrid; España. Institute for Advanced Research in Chemical Sciences; EspañaFil: Campillo, Nuria E.. Consejo Superior de Investigaciones Científicas. Centro de Investigaciones Biológicas; Españ

Deciphering the enzymatic target of a new family of antischistosomal agents bearing a quinazoline scaffold using complementary computational tools.

A previous phenotypic screening campaign led to the identification of a quinazoline derivative with promising in vitro activity against Schistosoma mansoni. Follow-up studies of the antischistosomal potential of this candidate are presented here. The in vivo studies in a S. mansoni mouse model show a significant reduction of total worms and a complete disappearance of immature eggs when administered concomitantly with praziquantel in comparison with the administration of praziquantel alone. This fact is of utmost importance because eggs are responsible for the pathology and transmission of the disease. Subsequently, the chemical optimisation of the structure in order to improve the metabolic stability of the parent compound was carried out leading to derivatives with improved drug-like properties. Additionally, the putative target of this new class of antischistosomal compounds was envisaged by using computational tools and the binding mode to the target enzyme, aldose reductase, was proposed

Design of New Dispersants Using Machine Learning and Visual Analytics

Artificial intelligence (AI) is an emerging technology that is revolutionizing the discovery of new materials. One key application of AI is virtual screening of chemical libraries, which enables the accelerated discovery of materials with desired properties. In this study, we developed computational models to predict the dispersancy efficiency of oil and lubricant additives, a critical property in their design that can be estimated through a quantity named blotter spot. We propose a comprehensive approach that combines machine learning techniques with visual analytics strategies in an interactive tool that supports domain experts’ decision-making. We evaluated the proposed models quantitatively and illustrated their benefits through a case study. Specifically, we analyzed a series of virtual polyisobutylene succinimide (PIBSI) molecules derived from a known reference substrate. Our best-performing probabilistic model was Bayesian Additive Regression Trees (BART), which achieved a mean absolute error of (Formula presented.) and a root mean square error of (Formula presented.), as estimated through 5-fold cross-validation. To facilitate future research, we have made the dataset, including the potential dispersants used for modeling, publicly available. Our approach can help accelerate the discovery of new oil and lubricant additives, and our interactive tool can aid domain experts in making informed decisions based on blotter spot and other key propertie

Identification of potential inhibitors of protein-protein interaction useful to fight against Ebola and other highly pathogenic viruses

16 p.-1 fig.-1 tab.Despite the efforts to develop new treatments against Ebola virus (EBOV) there is currently no antiviral drug licensed to treat patients with Ebola virus disease (EVD). Therefore, there is still an urgent need to find new drugs to fight against EBOV. In order to do this, a virtual screening was done on the druggable interaction between the EBOV glycoprotein (GP) and the host receptor NPC1 with a subsequent selection of compounds for further validation. This screening led to the identification of new small organic molecules with potent inhibitory action against EBOV infection using lentiviral EBOV-GP-pseudotype viruses. Moreover, some of these compounds have shown their ability to interfere with the intracellular cholesterol transport receptor NPC1 using an ELISA-based assay. These preliminary results pave the way to hit to lead optimization programs that lead to successful candidates.Funding from “la Caixa” Banking Foundation under the project code HR18-00469 is acknowledged. This research was partially supported through Instituto de Salud Carlos III (FIS PI 181007 and ISCIII-COV20/01007), CSIC (201980E024 and 202020E079), Spanish Ministry of Science and Innovation (RTI2018-097305-R-I00) and the European Commission Horizon 2020 Framework Programme (Project VIRUSCAN FETPROACT-2016 and VACDIVA-SFS-12-2019-1-862874).Peer reviewe

Subtly modulating glycogen synthase kinase 3 ß: Allosteric inhibitor development and their potential for the treatment of chronic diseases

Glycogen synthase kinase 3 ß (GSK-3ß) is a central target in several unmet diseases. To increase the specificity of GSK-3ß inhibitors in chronic treatments, we developed small molecules allowing subtle modulation of GSK-3ß activity. Design synthesis, structure¿activity relationships, and binding mode of quinoline-3-carbohydrazide derivatives as allosteric modulators of GSK-3ß are presented here. Furthermore, we show how allosteric binders may overcome the ß-catenin side effects associated with strong GSK-3ß inhibition. The therapeutic potential of some of these modulators has been tested in human samples from patients with congenital myotonic dystrophy type 1 (CDM1) and spinal muscular atrophy (SMA) patients. We found that compound 53 improves delayed myogenesis in CDM1 myoblasts, while compounds 1 and 53 have neuroprotective properties in SMA-derived cells. These findings suggest that the allosteric modulators of GSK-3ß may be used for future development of drugs for DM1, SMA, and other chronic diseases where GSK-3ß inhibition exhibits therapeutic effects.This work was financially supported by MINECO (grant no. SAF2012-37979-C03-01 and SAF2016-76693-R to A.M. and IJCI-2014-20767 to V.P.). CCHMC funds L.T. A.M. and C.G. are members of the CIB Intramural Program “Molecular Machines for Better Life” (MACBET).Peer Reviewe

Colonnes en béton armé renforcées de PRFV sous un chargement sismique simulé

Abstract : Steel and fiber-reinforced-polymer (FRP) materials have different mechanical and physical characteristics. High corrosion resistance, high strength to weight ratio, non-conductivity, favorable fatigue enable the FRP to be considered as alternative reinforcement for structures in harsh environment. Meanwhile, FRP bars have low modulus of elasticity and linear-elastic stress-strain curve. These features raise concerns about the applicability of using such materials as reinforcement for structures prone to earthquakes. The main demand for the structural members in structures subjected to seismic loads is dissipating energy without strength loss which is known as ductility. In the rigid frames, columns are expected to be the primary elements of energy dissipation in structures subjected to seismic loads. The present study addresses the feasibility of reinforced-concrete columns totally reinforced with glass-fiber-reinforced-polymer (GFRP) bars achieving reasonable strength and the drift requirements specified in various codes. Eleven full-scale reinforced concrete columns—two reinforced with steel bars (as reference specimens) and nine totally reinforced with GFRP bars—were constructed and tested to failure. The columns were tested under quasi-static reversed cyclic lateral loading and simultaneously subjected to compression axial load. The columns are 400 mm square cross-section with a shear span 1650 mm. The specimen simulates a column with 3.7 m in height in a typical building with the point of contra-flexure located at the column mid-height. The tested parameters were the longitudinal reinforcement ratio (0.63, 0.95 and 2.14), the spacing of the transverse stirrups (80, 100, 150), tie configuration (C1, C2, C3 and C4), and axial load level (20%, 30% and 40%). The test results clearly show that properly designed and detailed GFRP-reinforced concrete columns could reach high deformation levels with no strength degradation. An acceptable level of energy dissipation compared with steel-reinforced concrete columns is provided by GFRP reinforced concrete columns. The dissipated energy of GFRP reinforced concrete columns was 75% and 70% of the counter steel columns at 2.5% and 4% drift ratio respectively. High drift capacity achieved by the columns up to 10% with no significant loss in strength. The high drift capacity and acceptable dissipated energy enable the GFRP columns to be part of the moment resisting frames in regions prone to seismic activities. The experimental ultimate drift ratios were compared with the estimated drift ratios using the confinement Equation in CSA S806-12. It was found from the comparison that the confinement Equation underestimates values of the drift ratios thus the experimental drift ratios were used to modify transverse FRP reinforcement area in CSA S806-12. The hysteretic behavior encouraged to propose a design procedure for the columns to be part of the moderate ductile and ductile moment resisting frames. The development of design guidelines, however, depends on determining the elastic and inelastic deformations and on assessing the force modification factor and equivalent plastic-hinge length for GFRP-reinforced concrete columns. The experimental results of the GFRP-reinforced columns were used to justify the design guideline, proving the accuracy of the proposed design equations.L’acier et les matériaux à base de polymères renforcés de fibres (PRF) ont des caractéristiques physiques et mécaniques différentes. La résistance à la haute corrosion, le rapport résistance vs poids, la non-conductivité et la bonne résistance à la fatigue font des barres d’armature en PRF, un renforcement alternatif aux barres d’armature en acier, pour des structures dans des environnements agressifs. Cependant, les barres d’armature en PRF ont un bas module d’élasticité et une courbe contrainte-déformation sous forme linéaire. Ces caractéristiques soulèvent des problèmes d'applicabilité quant à l’utilisation de tels matériaux comme renforcement pour des structures situées en forte zone sismique. La principale exigence pour les éléments structuraux des structures soumises à des charges sismiques est la dissipation d'énergie sans perte de résistance connue sous le nom de ductilité. Dans les structures rigides de type cadre, on s'attend à ce que les colonnes soient les premiers éléments à dissiper l'énergie dans les structures soumises à ces charges. La présente étude traite de la faisabilité des colonnes en béton armé entièrement renforcées de barres d’armature en polymères renforcés de fibres de verre (PRFV), obtenant une résistance et un déplacement latéral raisonnable par rapport aux exigences spécifiées dans divers codes. Onze colonnes à grande échelle ont été fabriquées: deux colonnes renforcées de barres d'acier (comme spécimens de référence) et neuf colonnes renforcées entièrement de barres en PRFV. Les colonnes ont été testées jusqu’à la rupture sous une charge quasi-statique latérale cyclique inversée et soumises simultanément à une charge axiale de compression. Les colonnes ont une section carrée de 400 mm avec une portée de cisaillement de 1650 mm pour simuler une colonne de 3,7 m de hauteur dans un bâtiment typique avec le point d’inflexion situé à la mi-hauteur. Les paramètres testés sont : le taux d’armature longitudinal (0,63%, 0,95% et 2,14 %), l'espacement des étriers (80mm, 100mm, 150 mm), les différentes configurations (C1, C2, C3 et C4) et le niveau de charge axiale (20%, 30 % et 40%). Les résultats des essais montrent clairement que les colonnes en béton renforcées de PRFV et bien conçues peuvent atteindre des niveaux de déformation élevés sans réduction de résistance. Un niveau acceptable de dissipation d'énergie, par rapport aux colonnes en béton armé avec de l’armature en acier, est atteint par les colonnes en béton armé de PRFV. L'énergie dissipée des colonnes en béton armé de PRFV était respectivement de 75% et 70% des colonnes en acier à un rapport déplacement latéral de 2,5% et 4%. Un déplacement supérieur a été atteint par les colonnes en PRFV jusqu'à 10% sans perte significative de résistance. La capacité d’un déplacement supérieur et l’énergie dissipée acceptable permettent aux colonnes en PRFV de participer au moment résistant dans des régions sujettes à des activités sismiques. Les rapports des déplacements expérimentaux ultimes ont été comparés avec les rapports estimés en utilisant l’Équation de confinement du code CSA S806-12. À partir de la comparaison, il a été trouvé que l’Équation de confinement sous-estime les valeurs des rapports de déplacement, donc les rapports de déplacement expérimentaux étaient utilisés pour modifier la zone de renforcement transversal du code CSA S806-12. Le comportement hystérétique encourage à proposer une procédure de conception pour que les colonnes fassent partie des cadres rigides à ductilité modérée et résistant au moment. Cependant, l'élaboration de guides de conception dépend de la détermination des déformations élastiques et inélastiques et de l'évaluation du facteur de modification de la force sismique et de la longueur de la rotule plastique pour les colonnes en béton armé renforcées de PRFV. Les résultats expérimentaux des colonnes renforcées de PRFV étudiées ont été utilisés pour justifier la ligne directrice de conception, ce qui prouve l’efficacité des équations de conception proposées

COVID-19: Drug targets and potential treatments

92 p.-22 fig.-1 tab.-1 graph. abst.Currently, we are immersed in a pandemic caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which severely threatens public health worldwide. Until now, no drug or vaccine has been approved to treat the severe disease caused by this coronavirus, COVID-19. We will focus on the main virus-based and host-based targets that can guide medicinal chemistry efforts to discover new drugs for this devastating disease. In principle, all CoVs enzymes and proteins involved in viral replication and the control of host cellular machineries are potentially druggable targets in the search for therapeutic options for SARS-CoV-2. This perspective provides an overview of the main targets from a structural point of view, together with reported therapeutic compounds with activity against SARS-CoV-2 and/or other CoVs. Also, the role of innate immune response to coronavirus infection and the related therapeutic options will be presented.Funding from CSIC (201980E024 and 202020E103) is acknowledged. This research was partially supported through "la Caixa" Banking Foundation (HR18-00469), Instituto de Salud Carlos III (ISCIII-COV20/01007), Spanish Ministry of Science and Innovation (RTI2018-097305-R-I00), CONICYT-PCI (REDES190074 to D. R. and A. M.) and FONDECYT (11180604 to D.R.). I. M. was funded by H2020-MSCA-ITN-2017 (grant no. 765912), V. N. holds a pre-doctoral FPU grant (FPU16/04466) and J. U. was financed by FPI-SGIT2018-04.Peer reviewe