A survey of across-target bioactivity results of small molecules in PubChem

This work provides an analysis of across-target bioactivity results in the screening data deposited in PubChem. Two alternative approaches for grouping-related targets are used to examine a compound's across-target bioactivity. This analysis identifies compounds that are selectively active against groups of protein targets that are identical or similar in sequence. This analysis also identifies compounds that are bioactive across unrelated targets. Statistical distributions of compound' across-target selectivity provide a survey to evaluate target specificity of compounds by deriving and analyzing bioactivity profile across a wide range of biological targets for tested small molecules in PubChem. This work enables one to select target specific inhibitors, identify promiscuous compounds and better understand the biological mechanisms of target-small molecule interactions

Automated radiofrequency-based US measurement of common carotid intima-media thickness in RA patients treated with synthetic vs synthetic and biologic DMARDs

Objective. To compare the carotid intima-media thickness (IMT) assessed with automated radiofrequency-based US in RA patients treated with synthetic vs synthetic and biologic DMARDs and controls. Methods. Ninety-four RA patients and 94 sex-and age-matched controls were prospectively recruited at seven centres. Cardiovascular (CV) risk factors and co-morbidities, RA characteristics and therapy were recorded. Common carotid artery (CCA)-IMT was assessed in RA patients and controls with automated radiofrequency-based US by the same investigator at each centre. Results. Forty-five (47.9%) RA patients had been treated with synthetic DMARDs and 49 (52.1%) with synthetic and biologic DMARDs. There were no significant differences between the RA patients and controls in demographics, CV co-morbidities and CV disease. There were significantly more smokers among RA patients treated with synthetic and biologic DMARDs (P = 0.036). Disease duration and duration of CS and synthetic DMARD therapy was significantly longer in RA patients treated with synthetic and biologic DMARDs (P<0.0005). The mean CCA-IMT was significantly greater in RA patients treated only with synthetic DMARDs than in controls [591.4 (98.6) vs 562.1 (85.8); P = 0.035] and in RA patients treated with synthetic and biologic DMARDs [591.4 (98.6) vs 558.8 (95.3); P = 0.040). There was no significant difference between the mean CCA-IMT in RA patients treated with synthetic and biologic DMARDs and controls (P = 0.997). Conclusion. Our results suggest that radiofrequency-based measurement of CCA-IMT can discriminate between RA patients treated with synthetic DMARDs vs RA patients treated with synthetic and biologic DMARDs

Psychometric attributes of the DISC Predictive Scales

Introduction: This study was designed to evaluate the psychometric attributes and screening efficiency of a Spanish version of the Children Predictive Scales (DPS) against the Spanish Diagnostic Interview Schedule for Children (DISC-IV). Method: This pilot cross-sectional study included 61 children aged 9 to 14 years in a mainstream school. The following psychometric attributes were analyzed: acceptability, scale assumptions, internal consistency, and precision, as well the predictive validity (AUC). Results: The scale did not show ceiling or floor effects (6.4%, 1.3%, respectively). The internal consistency was high (α±=0.92), and the standard error of measurement was adequate (SEM=1.54). The overall DPS AUC was 0.72 against DISC IV corresponding diagnosis. Conclusion: The Spanish version of the DPS-4.32 seems to be a reliable and precise tool for screening mental health disorders in a school-age population

Cycloaddition Strategies for the Synthesis of Diverse Heterocyclic Spirocycles for Fragment-Based Drug Discovery.

In recent years the pharmaceutical industry has benefited from the advances made in fragment-based drug discovery (FBDD) with more than 30 fragment-derived drugs currently marketed or progressing through clinical trials. The success of fragment-based drug discovery is entirely dependent upon the composition of the fragment screening libraries used. Heterocycles are prevalent within marketed drugs due to the role they play in providing binding interactions; consequently, heterocyclic fragments are important components of FBDD libraries. Current screening libraries are dominated by flat, sp2-rich compounds, primarily owing to their synthetic tractability, despite the superior physicochemical properties displayed by more three-dimensional scaffolds. Herein, we report step-efficient routes to a number of biologically relevant, fragment-like heterocyclic spirocycles. The use of both electron-deficient and electron-rich 2-atom donors was explored in complexity-generating [3+2]-cycloadditions to furnish products in 3 steps from commercially available starting materials. The resulting compounds were primed for further fragment elaboration through the inclusion of synthetic handles from the outset of the syntheses

High-throughput characterization of fluid properties to predict droplet ejection for three-dimensional inkjet printing formulations

Inkjet printing has been used as an Additive Manufacturing (AM) method to fabricate three-dimensional (3D) structures. However, a lack of materials suitable for inkjet printing poses one of the key challenges that impedes industry from fully adopting this technology. Consequently, many industry sectors are required to spend significant time and resources on formulating new materials for an AM process, instead of focusing on product development. To achieve the spatially controlled deposition of a printed voxel in a predictable and repeatable fashion, a combination of the physical properties of the ‘ink’ material, print head design, and processing parameters is associated. This study demonstrates the expedited formulation of new inks through the adoption of a high-throughput screening (HTS) approach. Use of a liquid handler containing multi-pipette heads, to rapidly prepare inkjet formulations in a micro-array format, and subsequently measure the viscosity and surface tension for each in a high-throughput manner is reported. This automatic approach is estimated to be 15 times more rapid than conventional methods. The throughput is 96 formulations per 13.1 working hours, including sample preparation and subsequent printability determination. The HTS technique was validated by comparison with conventional viscosity and surface tension measurements, as well as the observation of droplet ejection during inkjet printing processes. Using this approach, a library of 96 acrylate/methacrylate materials was screened to identify the printability of each formulation at different processing temperatures. The methodology and the material database established using this HTS technique will allow academic and industrial users to rapidly select the most ideal formulation to deliver printability and a predicted processing window for a chosen application

Systematic mapping of cancer cell target dependencies using high-throughput drug screening in triple-negative breast cancer

While high-throughput drug screening offers possibilities to profile phenotypic responses of hundreds of compounds, elucidation of the cell context-specific mechanisms of drug action requires additional analyses. To that end, we developed a computational target deconvolution pipeline that identifies the key target dependencies based on collective drug response patterns in each cell line separately. The pipeline combines quantitative drug-cell line responses with drug-target interaction networks among both intended on- and potent off-targets to identify pharmaceutically actionable and selective therapeutic targets. To demonstrate its performance, the target deconvolution pipeline was applied to 310 small molecules tested on 20 genetically and phenotypically heterogeneous triple-negative breast cancer (TNBC) cell lines to identify cell line-specific target mechanisms in terms of cytotoxic and cytostatic drug target vulnerabilities. The functional essentiality of each protein target was quantified with a target addiction score (TAS), as a measure of dependency of the cell line on the therapeutic target. The target dependency profiling was shown to capture inhibitory information that is complementary to that obtained from the structure or sensitivity of the drugs. Comparison of the TAS profiles and gene essentiality scores from CRISPR-Cas9 knockout screens revealed that certain proteins with low gene essentiality showed high target addictions, suggesting that they might be functioning as protein groups, and therefore be resistant to single gene knock-out. The comparative analysis discovered protein groups of potential multi-target synthetic lethal interactions, for instance, among histone deacetylases (HDACs). Our integrated approach also recovered a number of well-established TNBC cell line-specific drivers and known TNBC therapeutic targets, such as HDACs and cyclin-dependent kinases (CDKs). The present work provides novel insights into druggable vulnerabilities for TNBC, and opportunities to identify multi-target synthetic lethal interactions for further studies. (C) 2020 The Author(s). Published by Elsevier B.V.Peer reviewe