QSAR study and molecular docking of benzimidazole derivatives as potent activators of AMP-activated protein kinase

Abstract3D-QSAR and molecular docking methods were performed on a set of 74 benzimidazole derivatives previously studied as activators of the AMP-activated protein kinase (AMPK), a protein that plays a key role in the regulation of cellular energy balance. Relative enzyme activity (REA) of 74 compounds was quantitatively modelled using multiple linear regression (MLR) and neuronal networks (NN). The proposed QSAR model provided statistically significant results (rMLR=0.89; rNN=0.95 and rCV=0.90) and was validated using the leave-one-out method. The general binding mode of benzimidazole derivatives to the AMPK binding site was explored using molecular docking, with a focus on the most active molecules of our set, compounds 19 and 25

Contribution to the MHD modeling in low speed radial flux AC machines with air-gaps filled with conductive fluids

This work deals with the modeling of the magnetohydrodynamic (MHD) phenomena in the air-gaps of low speed radial flux AC electrical machines filled with incompressible and electrically conductive fluids. The proposed model concerns laminar flows and it is based on a weak MHD coupling at the steady state regimes. The MHD power losses are evaluated and discussed. The model is easy to implement and could be a useful tool for the design and the optimization. An application to marine current turbine is considered

Automates et programmation par contraintes pour la planification de personnel

As soon as a structure is organized, the ability to put the right people at the right time is critical to satisfy the need of a department, a school or a company. We define personnel scheduling problems as the process of building, in an optimized manner, the personnel schedules. The aims of this thesis are to propose a mean to express those problems in a simple and automatic way, avoiding the user to interact with the technical aspects of the resolution. For that matter, we propose to mix the modeling power of automata with the efficiency and modularity of constraint programming for complex problem solving. Thus, we use the expressiveness of the finite multi-valued automata to model complex scheduling rules. Then, to make use of those built automata, we introduce a new filtering algorithm for multi-valued finite automata based on Lagrangian relaxation : multicost-regular. We also introduce a soft version of this constraint that has the ability to penalize violated rules defined by the automaton : soft-multicost-regular. The constraint model is automatically built. It is solved using the constraint library CHOCO and the whole modeling-solving process has been tested on realistic instances from ASAP and NRP10 libraries. The solution search is finally improved using specialized regret-based heuristics using the structure of multicost-regular and soft-multicost-regular.Dès lors qu'une structure est organisée, la capacité de placer les bonnes personnes au bon moment devient cruciale pour satisfaire les besoins d'un service, d'une école ou d'une entreprise. On définit les problèmes de planification de personnel comme le procédé consistant à construire de manière optimisée les emplois du temps de travail du personnel. La motivation de cette thèse est de proposer un moyen d'exprimer ces problèmes de manière simple et automatique, sans avoir à intervenir ensuite dans le processus de résolution. Pour cela, nous proposons de rassembler le pouvoir de modélisation des automates avec la capacité de la programmation par contraintes à résoudre efficacement des problèmes complexes. Le caractère expressif des automates est ainsi utilisé pour modéliser des règles de séquencement complexes. Puis, afin d'intégrer ces automates multi-pondérés dans un modèle de programmation par contraintes, nous introduisons un nouvel algorithme de filtrage basé sur la relaxation lagrangienne : multicost-regular. Nous présentons également une version souple de cette contrainte permettant de pénaliser les violations d'une règle modélisée par un tel automate : soft-multicost-regular. Le modèle contraintes basé sur ces contraintes est automatiquement construit. Il est résolu à l'aide de la librairie de contraintes CHOCO et à été testé sur des instances réalistes issues des librairies ASAP et NRP10. La recherche de solution est améliorée par l'utilisation d'heuristiques spécifiques basées sur les regrets et s'appuyant sur la structure des contraintes multicost-regular et soft-multicost-regular

Implementação e validação do método de quantificação de Ácido Propiónico por HPLC em produtos de padaria e pastelaria

O pão é uma das formas mais comuns do consumo de cereais, encontrando-se presente nos hábitos alimentares da população Portuguesa. De forma a prolongar o seu tempo de prateleira torna-se necessário a introdução de aditivos ao seu processamento, sendo o principal o ácido propiónico. Este composto não apresenta risco para a saúde do consumidor aquando adicionado dentro dos limites legislados tornando-se, assim, importante e necessário o controlo dos seus níveis nos alimentos. Deste modo, de forma a monitorizar os níveis de ácido propiónico nos géneros alimentícios, o presente trabalho teve como objetivo a implementação e validação de uma metodologia analítica para a determinação de ácido propióncio em amostras de pão e bolo de arroz por cromatografia líquida de alta eficiência (HPLC), no laboratório de Química da SGS Portugal. De forma a assegurar a integridade dos resultados analíticos obtidos foram avaliados parâmetros de validação como a linearidade, os limites de deteção e quantificação, a repetibilidade, a precisão intermédia e a exatidão. Os resultados mostram que o método é linear para uma gama de trabalho entre 25,0 e 400,0 mg/kg de ácido propiónico. O método permite detetar o analito a partir 2,7 mg/L e quantificá-lo a partir de 8,2 mg/L. O método de HPLC apresentou repetibilidade e precisão intermédia aceitáveis, uma vez que os respetivos coeficientes de variação foram inferiores a 5%. A exatidão do método foi determinada recorrendo a ensaios de recuperação, tendo-se obtido percentagens de recuperação entre 83 – 108%. Tendo em conta que estes parâmetros se encontram de acordo com os critérios estabelecidos para a validação de um método analítico, considera-se que o objetivo proposto foi cumprido

On Matrices, Automata, and Double Counting

Matrix models are ubiquitous for constraint problems. Many such problems have a matrix of variables M, with the same constraint defined by a finite-state automaton A on each row of M and a global cardinality constraint gcc on each column of M. We give two methods for deriving, by double counting, necessary conditions on the cardinality variables of the gcc constraints from the automaton A. The first method yields linear necessary conditions and simple arithmetic constraints. The second method introduces the cardinality automaton, which abstracts the overall behaviour of all the row automata and can be encoded by a set of linear constraints. We evaluate the impact of our methods on a large set of nurse rostering problem instances

Relaxation lagrangienne pour le filtrage d'une contrainte-automate à coûts multiples

Relaxation lagrangienne pour le filtrage d'une contrainte-automate à coûts multiple

Inverse Problem in Nondestructive Testing Using Arrayed Eddy Current Sensors

A fast crack profile reconstitution model in nondestructive testing is developed using an arrayed eddy current sensor. The inverse problem is based on an iterative solving of the direct problem using genetic algorithms. In the direct problem, assuming a current excitation, the incident field produced by all the coils of the arrayed sensor is obtained by the translation and superposition of the 2D axisymmetric finite element results obtained for one coil; the impedance variation of each coil, due to the crack, is obtained by the reciprocity principle involving the dyadic Green’s function. For the inverse problem, the surface of the crack is subdivided into rectangular cells, and the objective function is expressed only in terms of the depth of each cell. The evaluation of the dyadic Green’s function matrix is made independently of the iterative procedure, making the inversion very fast

Revisiting the tree Constraint

International audienceThis paper revisits the tree constraint introduced in [2] which partitions the nodes of a n-nodes, m-arcs directed graph into a set of node-disjoint anti-arborescences for which only certain nodes can be tree roots. We introduce a new filtering algorithm that enforces generalized arc-consistency in O(n + m) time while the original filtering algorithm reaches O(nm) time. This result allows to tackle larger scale problems involving graph partitioning

QSAR-driven screening uncovers and designs novel pyrimidine-4,6-diamine derivatives as potent JAK3 inhibitors

This study presents a robust and integrated methodology that harnesses a range of computational techniques to facilitate the design and prediction of new inhibitors targeting the JAK3/STAT pathway. This methodology encompasses several strategies, including QSAR analysis, pharmacophore modeling, ADMET prediction, covalent docking, molecular dynamics (MD) simulations, and the calculation of binding free energies (MM/GBSA). An efficacious QSAR model was meticulously crafted through the employment of multiple linear regression (MLR). The initial MLR model underwent further refinement employing an artificial neural network (ANN) methodology aimed at minimizing predictive errors. Notably, both MLR and ANN exhibited commendable performance, showcasing R2 values of 0.89 and 0.95, respectively. The model's precision was assessed via leave-one-out cross-validation (CV) yielding a Q2 value of 0.65, supplemented by rigorous Y-randomization. , The pharmacophore model effectively differentiated between active and inactive drugs, identifying potential JAK3 inhibitors, and demonstrated validity with an ROC value of 0.86. The newly discovered and designed inhibitors exhibited high inhibitory potency, ranging from 6 to 8, as accurately predicted by the QSAR models. Comparative analysis with FDA-approved Tofacitinib revealed that the new compounds exhibited promising ADMET properties and strong covalent docking (CovDock) interactions. The stability of the new discovered and designed inhibitors within the JAK3 binding site was confirmed through 500 ns MD simulations, while MM/GBSA calculations supported their binding affinity. Additionally, a retrosynthetic study was conducted to facilitate the synthesis of these potential JAK3/STAT inhibitors. The overall integrated approach demonstrates the feasibility of designing novel JAK3/STAT inhibitors with robust efficacy and excellent ADMET characteristics that surpass Tofacitinib by a significant margin

Study of the feasibility of converting biomass from phytotechnology into biorefinery : Case of a hyperaccumulator plant (Noccaea caerulescens) and a woody plant (Salix viminalis)

La phytoremédiation est un concept pour la dépollution et de réhabilitation des sols et/ou de friches industrielles contaminés par des éléments traces métalliques (ETMs), utilisant les végétaux pour absorber ou immobiliser les contaminants en présence des organismes microbiens de la rhizosphère. Cette technique a pour conséquence une production de biomasse plus ou moins contaminée qu’il est nécessaire de traiter et également de valoriser. Cependant, la présence d’ETMs peut être problématique dans une approche de conversion en bioraffinerie. Pour répondre à cette question, deux espèces ont été étudiées : une plante herbacée hyperaccumulatrice (Noccaea caerulescens) et un ligneux (Salix viminalis). Deux prétraitements ont été sélectionnés pour cette étude : les prétraitements par explosion vapeur et organosolv, en appliquant différentes conditions opératoires, afin (1) de suivre la distribution des ETMs au cours du traitement, (2) de purifier la matière lignocellulosique et (3) d’évaluer l’effet des ETMs sur les étapes ultérieures d’hydrolyse enzymatique et de fermentation. Pour le prétraitement organosolv la majeure partie des ETMs est récupérée dans le résidu solide cellulosique alors que par explosion à la vapeur, les ETMs sont extraits en grande partie dans les effluents aqueux du traitement. La présence d’ETMs dans les pâtes cellulosiques et les hydrolysats ne montre pas d’effet significatif sur la cinétique d’hydrolyse enzymatique et de fermentation. Concernant spécifiquement Noccaea caerulescens des teneurs relativement importantes en pectines ont été observées, ce qui ouvre des perspectives intéressantes pour la valorisation de cette plante par la production d’un biopolymère d’intérêt industriel. Finalement, les résultats obtenus montrent qu’il serait possible de combiner réhabilitation des sols et valorisation en bioraffinerie de biomasses issues de phytotechnologies soit pour la production du bioéthanol ou la production de molécules plateformePhytoremediation is a concept for the depollution and rehabilitation of soils and/or industrial wastelands contaminated by metal trace elements (MTEs), using plants to absorb or immobilize contaminants in the presence of microbial organisms in the rhizosphere. This technique results in a more or less contaminated biomass production that must be treated and also recovered. However, the presence of MTEs can be an issue in a biorefinery conversion approach. To address this question, two species were studied: an hyperaccumulator herbaceous plant (Noccaea caerulescens) and a woody plant (Salix viminalis). Two pre-treatments were selected for this study: steam explosion and organosolv pre-treatments, applying different operating conditions, in order to (1) monitor the distribution of MTEs during the process, (2) purify lignocellulosic material and (3) evaluate the effect of MTEs on subsequent enzymatic hydrolysis and fermentation steps. For organosolv pretreatment, most of the MTEs are recovered in the solid cellulosic residue while by steam explosion, MTEs are mostly extracted in the aqueous effluents of the treatment. The presence of MTEs in cellulosic pastes and hydrolysates does not show a significant effect on the kinetics of enzymatic hydrolysis and fermentation. Concerning specifically Noccaea caerulescens, the plant contains relatively high levels of pectins, which opens up interesting prospects for the valorization of this plant through the production of a biopolymer of industrial interest. Finally, the results obtained show that it would be possible to combine soil rehabilitation and biorefinery valorization of biomasses from phytotechnologies for either bioethanol production or the production of platform molecule