Optimization of diarylazines as anti-HIV agents with dramatically

Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants.Fil: Bollini, Mariela. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cisneros, José A.. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados Unido

Transition to the Non-Clinical Drug Development Principles and Rules of the Eurasian Economic Union: Changes, Challenges, and Prospects

It is strategically critical to secure pharmaceutical independence for Russia by developing the industry using the latest achievements in science and technology. The development of nationally and internationally competitive medicines calls for the harmonisation of national and international requirements for non-clinical and clinical studies.In this interview, Alexander A. Spasov, Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Full Professor, Head of the Department of Pharmacology and Bioinformatics of the Volgograd State Medical University, voices his authoritative opinion on the changes to the regulatory requirements for non-clinical and clinical studies of medicinal products that are related to the transition of the Russian Federation to the Eurasian Economic Union marketing authorisation requirements. Alexander A. Spasov touches upon the development and application potential of cutting-edge research methods (in silico, human cell-based and alternative animal-based methods) for the creation and implementation of more reliable and rapid test systems for pharmacology and toxicity studies

EFFECTIVENESS OF “POLYKATAN” GEL IN CASE OF TRAUMATIC STOMATITIS

Traumatic stomatitis oforalmucosa in rabbits has been studied. Stimulatory effect ofmagnesium-containing "Polykatan” gel on thermal burn in comparison with "Polykatan" solution has been revealed. "Polykatan" solution based on solution of clean bischofite mineral is used in the therapeutic dentistry

Deep learning-based i-EEG classification with convolutional neural networks for drug-target interaction prediction

Drug-target interaction (DTI) prediction has become a foundational task in drug repositioning, polypharmacology, drug discovery, as well as drug resistance and side-effect prediction. DTI identification using machine learning is gaining popularity in these research areas. Through the years, numerous deep learning methods have been proposed for DTI prediction. Nevertheless, prediction accuracy and efficiency remain key challenges. Pharmaco-electroencephalogram (pharmaco-EEG) is considered valuable in the development of central nervous system-active drugs. Quantitative EEG analysis demonstrates high reliability in studying the effects of drugs on the brain. Earlier preclinical pharmaco-EEG studies showed that different types of drugs can be classified according to their mechanism of action on neural activity. Here, we propose a convolutional neural network for EEG-mediated DTI prediction. This new approach can explain the mechanisms underlying complicated drug actions, as it allows the identification of similarities in the mechanisms of action and effects of psychotropic drugs

Antidiabetogenic Features of Benzimidazoles

Literature data on the insulinogenic effect of 2-aminobenzimidazole prompted us to investigate its novel derivatives, particularly those containing an additional fused cycle in C1,2-α position, including imidazole, dihydroimidazole, or tetrahydropyrimidine ring. Consensus analysis of the hypoglycemic effect of these compounds performed with IT Microcosm and PASS system revealed that activity is mostly characteristic for N9-2,3-dihydroimidazo[1,2-a]benzimidazole derivatives. Substructural analysis of hypoglycemic activity identified substituents that determine the greatest pharmacological effect. According to the in silico assessment of the ADME properties, RU-254 was nominated as a lead compound due to the most optimal calculated and experimental activity and pharmacokinetic parameters. Preclinical studies have shown that identified compound has a pronounced insulinogenic effect and hypoglycemic effect, both in intact animals and in animals with experimental diabetes mellitus. RU-254 also reduces the level of glycated hemoglobin upon chronic administration, slightly decreases the activity of DPP-4, and increases the average number of Langerhans islets in the pancreas. Pharmaceutical drug formulation of RU-254 was developed and investigated for pharmacokinetic, pharmacodynamic, and toxicological properties. The dosage form of the drug under the name limiglidol (compound RU-254, diabenol) was evaluated in the full cycle of clinical studies that confirmed the safety, tolerability, and prominent antidiabetic properties of the drug

VAESim: A probabilistic approach for self-supervised prototype discovery

In medical image datasets, discrete labels are often used to describe a continuous spectrum of conditions, making unsupervised image stratification a challenging task. In this work, we propose VAESim, an architecture for image stratification based on a conditional variational autoencoder. VAESim learns a set of prototypical vectors during training, each associated with a cluster in a continuous latent space. We perform a soft assignment of each data sample to the clusters and reconstruct the sample based on a similarity measure between the sample embedding and the prototypical vectors. to update the prototypical embeddings, we use an exponential moving average of the most similar representations between actual prototypes and samples in the batch size. We test our approach on the MNIST handwritten digit dataset and the pneumoniaMNIST medical benchmark dataset, where we show that our method outperforms baselines in terms of kNN accuracy (up to +15% improvement in performance) and performs at par with classification models trained in a fully supervised way. our model also outperforms current end-to-end models for unsupervised stratification

Condensed Benzimidazoles Are a Novel Scaffold for Antioxidant Agents’ Search and Development

Taking into account that the imidazole ring has π-electron redundancy, condensed benzimidazole derivatives have attracted our attention as a promising class for the search for antioxidant substances. Synthesis was carried out, and information on the antioxidant activity of imidazo- and tetrahydropyrimido benzimidazoles was provided. Highly active antioxidant substance enoxifol has been revealed. The data on the synthesis and study of the pharmacodynamic, pharmacokinetic, and toxicological properties of the new antioxidant compound enoxifol are presented. The antioxidant activity of the compound is due to its ability to inactivate superoxide, hydroxyl, and peroxyl radicals, thereby reducing the overall oxidation rate due to a decrease in the total initiation rate. It has been shown that enoxifol has hepatoprotector, antihypoxic, cerebroprotective, nootropic, stress-protective, neuropsychotropic, actoprotective, cardioprotective, antiaggregant, and antithrombogenic properties and is able to prevent rheological disorders in diabetes mellitus

Search for compounds with antioxidant and antiradical activity among N9-substituted 2-(biphenyl-4-yl)imidazo[1,2-a]benzimidazoles

The aim of this study was to synthesize and investigate in vitro antioxidant activity of promising novel compounds: 2-(biphenyl-4-yl)imidazo[1,2-a]benzimidazole

An Overview of the GEOS-5 Aerosol Reanalysis

GEOS-5 is the latest version of the NASA Global Modeling and Assimilation Office (GMAO) earth system model. GEOS-5 contains components for atmospheric circulation and composition (including data assimilation), ocean circulation and biogeochemistry, and land surface processes. In addition to traditional meteorological parameters, GEOS-5 includes modules representing the atmospheric composition, most notably aerosols and tropospheric/stratospheric chemical constituents, taking explicit account of the impact of these constituents on the radiative processes of the atmosphere. MERRA is a NASA meteorological reanalysis for the satellite era (1979-present) using GEOS-5. This project focuses on historical analyses of the hydrological cycle on a broad range of weather and climate time scales. As a first step towards an integrated Earth System Analysis (IESA), the GMAO is extending MERRA with reanalyses for other components of the earth system: land, ocean, bio-geochemistry and atmospheric constituents. In this talk we will present results from the MERRA-driven aerosol reanalysis covering the Aqua period (2003-present). The assimilation of Aerosol Optical Depth (AOD) in GEOS-5 involves very careful cloud screening and homogenization of the observing system by means of a Neural Net scheme that translates MODIS radiances into AERONET calibrated AOD. These measurements are further quality controlled using an adaptive buddy check scheme, and assimilated using the Local Displacement Ensemble (LDE) methodology. For this reanalysis, GEOS-5 runs at a nominal 50km horizontal resolution with 72 vertical layers (top at approx. 8Skm). GEOS-5 is driven by daily biomass burning emissions derived from MODIS fire radiative power retrievals. We will present a summary of our efforts to validate such dataset. The GEOS-5 assimilated aerosol fields are first validated by comparison to independent in-situ measurements (AERONET and PM2.5 surface concentrations). In order to asses aerosol absorption on a global scale, we perform a detailed radiative transfer calculation to simulate the UV aerosol index, comparing our results to OMI measurements. By simulating aerosol attenuated backscatter, we use CALIPSO measurements to evaluate the vertical structure of our aerosol estimates, in particular in regions where we have larger discrepancies with OMI. Finally, the consistency of our AOD estimates with estimates from MISR, MODIS/Deep Blue, OMI and PARASOL will be briefly discussed

Structure-based evaluation of C5 derivatives in the catechol diether series targeting HIV-1 reverse transcriptase

Using a computationally driven approach, a class of inhibitors with picomolar potency known as the catechol diethers were developed targeting the non-nucleoside-binding pocket of HIV-1 reverse transcriptase. Computational studies suggested that halogen-bonding interactions between the C5 substituent of the inhibitor and backbone carbonyl of conserved residue Pro95 might be important. While the recently reported crystal structures of the reverse transcriptase complexes confirmed the interactions with the non-nucleoside-binding pocket, they revealed the lack of a halogen-bonding interaction with Pro95. To understand the effects of substituents at the C5 position, we determined additional crystal structures with 5-Br and 5-H derivatives. Using comparative structural analysis, we identified several conformations of the ethoxy uracil dependent on the strength of a van der Waals interaction with the Cγ of Pro95 and the C5 substitution. The 5-Cl and 5-F derivatives position the ethoxy uracil to make more hydrogen bonds, whereas the larger 5-Br and smaller 5-H position the ethoxy uracil to make fewer hydrogen bonds. EC50 values correlate with the trends observed in the crystal structures. The influence of C5 substitutions on the ethoxy uracil conformation may have strategic value, as future derivatives can possibly be modulated to gain additional hydrogen-bonding interactions with resistant variants of reverse transcriptase.Fil: Frey, Kathleen M.. University of Yale; Estados UnidosFil: Gray, William T.. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale; Estados UnidosFil: Bollini, Mariela. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gallardo Macias, Ricardo. University of Yale; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados Unido