Estudio del reconocimiento molecular de un portador movil neutro usado como electrodo all solid state a nitrato

En este trabajo se valora un ESI de membrana liquida plastificada con la 1-furoil-3,3-dietiltiourea como portadormóvil neutro, el tributilfosfato como plastificante y cloruro de polivinilo como matriz sobre un soporte conductor sensible a plomo y nitrato (a este ultimo una vez agotado el tiempo de vida del ESI a plomo). Para el mismo portador se manifiesta dos mecanismos de respuesta muy eficaces.El ESI a Pb2+ presenta una respuesta lineal en el rango de concentración de 10-6 –10-3 mol/dm3, con pendiente de29,6 mV/déc, el tiempo de respuesta obtenido fue de 20seg. Para el ESI a NO3 la pendiente fue sobrenernstiana de-63.14 mV/déc y un tiempo de respuesta de 20 seg.Se presentan los parámetros de calibración, así como lasMicroscopía Electrónica de Barrido (MEB) de las membranasdel ESI sensible al catión plomo (II) y vistas de éstascuando pierde su sensibilidad a este ion y comienzan aresponder a su segundo primario por un segundo mecanismode respuesta. El ESI a Pb2+ es usado por más de 1 es. Los resultados del cálculo teórico justifican los mecanismos derespuesta a ambos iones

ANN multiscale model of anti-HIV Drugs activity vs AIDS prevalence in the US at county level based on information indices of molecular graphs and social networks

[Abstract] This work is aimed at describing the workflow for a methodology that combines chemoinformatics and pharmacoepidemiology methods and at reporting the first predictive model developed with this methodology. The new model is able to predict complex networks of AIDS prevalence in the US counties, taking into consideration the social determinants and activity/structure of anti-HIV drugs in preclinical assays. We trained different Artificial Neural Networks (ANNs) using as input information indices of social networks and molecular graphs. We used a Shannon information index based on the Gini coefficient to quantify the effect of income inequality in the social network. We obtained the data on AIDS prevalence and the Gini coefficient from the AIDSVu database of Emory University. We also used the Balaban information indices to quantify changes in the chemical structure of anti-HIV drugs. We obtained the data on anti-HIV drug activity and structure (SMILE codes) from the ChEMBL database. Last, we used Box-Jenkins moving average operators to quantify information about the deviations of drugs with respect to data subsets of reference (targets, organisms, experimental parameters, protocols). The best model found was a Linear Neural Network (LNN) with values of Accuracy, Specificity, and Sensitivity above 0.76 and AUROC > 0.80 in training and external validation series. This model generates a complex network of AIDS prevalence in the US at county level with respect to the preclinical activity of anti-HIV drugs in preclinical assays. To train/validate the model and predict the complex network we needed to analyze 43,249 data points including values of AIDS prevalence in 2,310 counties in the US vs ChEMBL results for 21,582 unique drugs, 9 viral or human protein targets, 4,856 protocols, and 10 possible experimental measures.Ministerio de Educación, Cultura y Deportes; AGL2011-30563-C03-0

Modeling complex metabolic reactions, ecological systems, and financial and legal networks with MIANN models based on Markov-Wiener node descriptors

[Abstract] The use of numerical parameters in Complex Network analysis is expanding to new fields of application. At a molecular level, we can use them to describe the molecular structure of chemical entities, protein interactions, or metabolic networks. However, the applications are not restricted to the world of molecules and can be extended to the study of macroscopic nonliving systems, organisms, or even legal or social networks. On the other hand, the development of the field of Artificial Intelligence has led to the formulation of computational algorithms whose design is based on the structure and functioning of networks of biological neurons. These algorithms, called Artificial Neural Networks (ANNs), can be useful for the study of complex networks, since the numerical parameters that encode information of the network (for example centralities/node descriptors) can be used as inputs for the ANNs. The Wiener index (W) is a graph invariant widely used in chemoinformatics to quantify the molecular structure of drugs and to study complex networks. In this work, we explore for the first time the possibility of using Markov chains to calculate analogues of node distance numbers/W to describe complex networks from the point of view of their nodes. These parameters are called Markov-Wiener node descriptors of order kth (Wk). Please, note that these descriptors are not related to Markov-Wiener stochastic processes. Here, we calculated the Wk(i) values for a very high number of nodes (>100,000) in more than 100 different complex networks using the software MI-NODES. These networks were grouped according to the field of application. Molecular networks include the Metabolic Reaction Networks (MRNs) of 40 different organisms. In addition, we analyzed other biological and legal and social networks. These include the Interaction Web Database Biological Networks (IWDBNs), with 75 food webs or ecological systems and the Spanish Financial Law Network (SFLN). The calculated Wk(i) values were used as inputs for different ANNs in order to discriminate correct node connectivity patterns from incorrect random patterns. The MIANN models obtained present good values of Sensitivity/Specificity (%): MRNs (78/78), IWDBNs (90/88), and SFLN (86/84). These preliminary results are very promising from the point of view of a first exploratory study and suggest that the use of these models could be extended to the high-throughput re-evaluation of connectivity in known complex networks (collation)

Combining ensemble eearning with a fragment-based topological approach to generate new molecular diversity in drug discovery: In silico design of Hsp90 inhibitors

Machine learning methods have revolutionized modern science, providing fast and accurate solutions to multiple problems. However, they are commonly treated as "black boxes". Therefore, in important scientific fields such as medicinal chemistry and drug discovery, machine learning methods are restricted almost exclusively to the task of performing predictions of large and heterogeneous data sets of chemicals. The lack of interpretability prevents the full exploitation of the machine learning models as generators of new chemical knowledge. This work focuses on the development of an ensemble learning model for the prediction and design of potent dual heat shock protein 90 (Hsp90) inhibitors. The model displays accuracy higher than 80% in both training and test sets. To use the ensemble model as a generator of new chemical knowledge, three steps were followed. First, a physicochemical and/or structural interpretation was provided for each molecular descriptor present in the ensemble learning model. Second, the term "pseudolinear equation" was introduced within the context of machine learning to calculate the relative quantitative contributions of different molecular fragments to the inhibitory activity against the two Hsp90 isoforms studied here. Finally, by assembling the fragments with positive contributions, new molecules were designed, being predicted as potent Hsp90 inhibitors. According to Lipinski's rule of five, the designed molecules were found to exhibit potentially good oral bioavailability, a primordial property that chemicals must have to pass early stages in drug discovery. The present approach based on the combination of ensemble learning and fragment-based topological design holds great promise in drug discovery, and it can be adapted and applied to many different scientific disciplines

PTML Modeling for Pancreatic Cancer Research: In Silico Design of Simultaneous Multi-Protein and Multi-Cell Inhibitors

Pancreatic cancer (PANC) is a dangerous type of cancer that is a major cause of mortality worldwide and exhibits a remarkably poor prognosis. To date, discovering anti-PANC agents remains a very complex and expensive process. Computational approaches can accelerate the search for anti-PANC agents. We report for the first time two models that combined perturbation theory with machine learning via a multilayer perceptron network (PTML-MLP) to perform the virtual design and prediction of molecules that can simultaneously inhibit multiple PANC cell lines and PANC-related proteins, such as caspase-1, tumor necrosis factor-alpha (TNF-alpha), and the insulin-like growth factor 1 receptor (IGF1R). Both PTML-MLP models exhibited accuracies higher than 78%. Using the interpretation from one of the PTML-MLP models as a guideline, we extracted different molecular fragments desirable for the inhibition of the PANC cell lines and the aforementioned PANC-related proteins and then assembled some of those fragments to form three new molecules. The two PTML-MLP models predicted the designed molecules as potentially versatile anti-PANC agents through inhibition of the three PANC-related proteins and multiple PANC cell lines. Conclusions: This work opens new horizons for the application of the PTML modeling methodology to anticancer research