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The exploration of chemical space is a fundamental aspect of chemoinformatics, particularly when one explores a large compound data set to relate chemical structures with molecular properties. In this study, we extend our previous work on chemical space visualization at the pharmacophoric level. Instead of using conventional binary classification of affinity (active vs inactive), we introduce a refined approach that categorizes compounds into four distinct classes based on their activity levels: super active, very active, active, and inactive. This classification enriches the color scheme applied to pharmacophore space, where the color representation of a pharmacophore hypothesis is driven by the associated compounds. Using the BCR‐ABL tyrosine kinase as a case study, we identified intriguing regions corresponding to pharmacophore activity discontinuities, providing valuable insights for structure‐activity relationships analysis. [ABSTRACT FROM AUTHOR]

Drug-recalcitrant infections are a leading global-health concern. Bacterial cells benefit from phenotypic variation, which can suggest effective antimicrobial strategies. However, probing phenotypic variation entails spatiotemporal analysis of individual cells that is technically challenging, and hard to integrate into drug discovery. In this work, we develop a multi-condition microfluidic platform suitable for imaging two-dimensional growth of bacterial cells during transitions between separate environmental conditions. With this platform, we implement a dynamic single-cell screening for pheno-tuning compounds, which induce a phenotypic change and decrease cell-to-cell variation, aiming to undermine the entire bacterial population and make it more vulnerable to other drugs. We apply this strategy to mycobacteria, as tuberculosis poses a major public-health threat. Our lead compound impairs Mycobacterium tuberculosis via a peculiar mode of action and enhances other anti-tubercular drugs. This work proves that harnessing phenotypic variation represents a successful approach to tackle pathogens that are increasingly difficult to treat. Tuberculosis is a major global health threat. Here, the authors develop a single-cell drug discovery approach and identify a compound that tunes bacterial phenotypic variation. This enhances the activity of anti-tubercular drugs against the pathogen. [ABSTRACT FROM AUTHOR]

This paper presents a novel approach called Pharmacophore Activity Delta for extracting outstanding pharmacophores from a chemogenomic dataset, with a specific focus on a kinase target known as BCR-ABL. The method involves constructing a Hasse diagram, referred to as the pharmacophore network, by utilizing the subgraph partial order as an initial step, leading to the identification of pharmacophores for further evaluation. A pharmacophore is classified as a 'Pharmacophore Activity Delta' if its capability to effectively discriminate between active vs inactive molecules significantly deviates (by at least δ standard deviations) from the mean capability of its related pharmacophores. Among the 1479 molecules associated to BCR-ABL binding data, 130 Pharmacophore Activity Delta were identified. The pharmacophore network reveals distinct regions associated with active and inactive molecules. The study includes a discussion on representative key areas linked to different pharmacophores, emphasizing structure–activity relationships. [ABSTRACT FROM AUTHOR]

Maximum common substructures (MCS) have received a lot of attention in the chemoinformatics community. They are typically used as a similarity measure between molecules, showing high predictive performance when used in classification tasks, while being easily explainable substructures. In the present work, we applied the Pairwise Maximum Common Subgraph Feature Generation (PMCSFG) algorithm to automatically detect toxicophores (structural alerts) and to compute fingerprints based on MCS. We present a comparison between our MCS‐based fingerprints and 12 well‐known chemical fingerprints when used as features in machine learning models. We provide an experimental evaluation and discuss the usefulness of the different methods on mutagenicity data. The features generated by the MCS method have a state‐of‐the‐art performance when predicting mutagenicity, while they are more interpretable than the traditional chemical fingerprints. [ABSTRACT FROM AUTHOR]

In this work, we propose to analyze the potential of a new type of pharmacophoric descriptors coupled to a novel feature transformation technique, called Weight‐Matrix Learning (WML, based on a feed‐forward neural network). The application concerns virtual screening on a tyrosine kinase named BCR‐ABL. First, the compounds were described using three different families of descriptors: our new pharmacophoric descriptors, and two circular fingerprints, ECFP4 and FCFP4. Afterwards, each of these original molecular representations were transformed using either an unsupervised WML method or a supervised one. Finally, using these transformed representations, K‐Means clustering algorithm was applied to automatically partition the molecules. Combining our pharmacophoric descriptors with supervised Weight‐Matrix Learning (SWMLR) leads to clearly superior results in terms of several quality measures. [ABSTRACT FROM AUTHOR]

This article introduces a new type of structural fragment called a geometrical pattern. Such geometrical patterns are defined as molecular graphs that include a labelling of atoms together with constraints on interatomic distances. The discovery of geometrical patterns in a chemical dataset relies on the induction of multiple decision trees combined in random forests. Each computational step corresponds to a refinement of a preceding set of constraints, extending a previous geometrical pattern. This paper focuses on the mutagenicity of chemicals via the definition of structural alerts in relation with these geometrical patterns. It follows an experimental assessment of the main geometrical patterns to show how they can efficiently originate the definition of a chemical feature related to a chemical function or a chemical property. Geometrical patterns have provided a valuable and innovative approach to bring new pieces of information for discovering and assessing structural characteristics in relation to a particular biological phenotype. [ABSTRACT FROM AUTHOR]

Constraint-based pattern discovery is at the core of numerous data mining tasks. Patterns are extracted with respect to a given set of constraints (frequency, closedness, size, etc). In practice, many constraints require threshold values whose choice is often arbitrary. This difficulty is even harder when several thresholds are required and have to be combined. Moreover, patterns barely missing a threshold will not be extracted even if they may be relevant. The paper advocates the introduction of softness into the pattern discovery process. By using Constraint Programming, we propose efficient methods to relax threshold constraints as well as constraints involved in patterns such as the top- k patterns and the skypatterns. We show the relevance and the efficiency of our approach through a case study in chemoinformatics for discovering toxicophores. [ABSTRACT FROM AUTHOR]

A convenient four partners, three-step, of 2-alkyl(dialkyl)aminoquinazolin-4(3 H)-ones, starting from aniline derivatives, is reported. This method allowed us to prepare easily a library of quinazolinone compounds of pharmaceutical interest. [ABSTRACT FROM AUTHOR]

ABSTRACT Thiophene derivatives, a class of compounds widely used in products such as pharmaceuticals, agrochemicals or dyestuffs, represent chemicals of concern. Indeed, the thiophene ring is often considered as a structural moiety that may be involved in toxic effects in humans. We primarily focus on the genotoxic/mutagenic and carcinogenic potentials of the methyl 3-amino-4-methylthiophene-2-carboxylate (1), a precursor of the articaine local anesthetic (4) which falls within the scope of the European REACH (Registration, Evaluation, Authorisation and restriction of CHemicals) legislation. To discern some structure-toxicity relationships, we also studied two related compounds, namely the 3-amino 4-methylthiophene (2) and the 2-acetyl 4-chlorothiophene (3). Techniques employed to assess mutagenic and DNA-damaging effects involved the Salmonella mutagenicity assay (or Ames test) and the single-cell gel electrophoresis assay (or Comet assay). In the range of tested doses, none of these derivatives led to a positive response in the Ames tests and DNA damage was only observed in the Comet assay after high concentration exposure of 2. The study of their carcinogenic potential using the in vitro SHE (Syrian Hamster Embryo) cell transformation assay (CTA) highlighted the activity of compound 2. A combination of experimental data with in silico predictions of the reactivity of thiophene derivatives towards cytochrome P450 (CYP450), enabled us to hypothesize possible pathways leading to these toxicological profiles. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Three quantitative structure–activity relationship (QSAR) models were evaluated for their power to predict the toxicity of chemicals in two datasets: (1) EPAFHM (US Environmental Protection Agency—Fathead Minnow) and (2) derivatives having a high production volume (HPV), as compiled by the European Chemical Bureau. For all three QSAR models, the quality of the predictions was found to be highly dependent on the mode of action of the chemicals. An analysis of outliers from the three models gives some clues for improving the QSAR models. Two classification methods, Toxtree and a Bayesian approach with fingerprints as descriptors, were also analyzed. Predictions following the Toxtree classification for narcosis were good, especially for the HPV set. The learning model (Bayesian approach) produced interesting results for the EPAFHM dataset but gave lower quality predictions for the HPV set. [ABSTRACT FROM AUTHOR]

Background and Purpose: Human and rat 5-HT(7) receptors were studied with a particular emphasis on the molecular interactions involved in ligand binding, searching for an explanation to the interspecies selectivity observed for a set of compounds. We performed affinity studies, molecular modelling and site-directed mutagenesis, with special focus on residue Phe(7.38) of the human 5-HT(7) receptor [Cys(7.38) in rat].Experimental Approach: Competition binding studies were performed for seven 5-HT(7) receptor ligands at three different 5-HT(7) receptors. The functional behaviour was evaluated by measuring 5-carboxytryptamine-stimulated cAMP production. Computational simulations were carried out to explore the structural bases in ligand binding observed for these compounds.Key Results: Competition experiments showed a remarkable selectivity for the human receptor when compared with the rat receptor. These results indicate that mutating Cys to Phe at position 7.38 profoundly affects the binding affinities at the 5-HT(7) receptor. Computational simulations provide a structural interpretation for this key finding. Pharmacological characterization of compounds mr25020, mr25040 and mr25053 revealed a competitive antagonistic behaviour. Compounds mr22423, mr22433, mr23284 and mr25052 behaved as partial agonists.Conclusions and Implications: We propose that the interspecies difference in binding affinities observed for the compounds at human and rat 5-HT(7) receptors is due to the nature of the residue at position 7.38. Our molecular modelling simulations suggest that Phe(7.38) in the human receptor is integrated in the hydrophobic pocket in the central part of the binding site [Phe(6.51)-Phe(6.52)] and allows a tighter binding of the ligands when compared with the rat receptor. [ABSTRACT FROM AUTHOR]

Fifteen new thieno[2,3-b ]- and thieno (3,4-b]pyrrolizines were synthesized and tested against two protein kinases, CDK1/cyclin B and GSK-3. Among these compounds, 3-(3-hydroxy-4-methoxyphenyl)-8H-thieno [2,3-b] pyrrolizin- 8-one 4g was identified as a moderate inhibitor of these kinases. Its molecular modeling study brought to the fore the pivotal role of the 2-methoxyphenol grouping and the interest in replacing it by bioisosteric moieties in future pharmacomodulations. [ABSTRACT FROM AUTHOR]

Background: Pulmonary endothelium is an early upstream hemodynamic target of left ventricular dysfunction. Interleukin 6 (IL-6) is a pro-inflammatory cytokine reported to increase in congestive heart failure (CHF) patients.Aims: We sought to determine the origin of IL-6, IL-6 receptor (IL-6R) and gp130 in experimental CHF.Methods: We used rats with coronary artery ligation as an experimental model of either compensated or decompensated heart failure. Lung and aorta samples were analysed by RT-PCR, ELISA and immunohistochemistry for IL-6 and its receptors.Results: IL-6 mRNA expression increased in the lung of rats with decompensated heart failure and was positively correlated with infarct severity whereas IL-6R mRNA decreased in the lung of myocardial infarction rats and gp130 mRNA remained unchanged. In contrast, there were no changes in IL-6 mRNA expression in the aorta and left ventricular myocardium. IL-6 peptide content as determined by ELISA and Western Blot in lung tissue was 2-fold higher in decompensated heart failure as compared to control rats. These data were confirmed by immunohistochemistry showing a preferential endothelial localization of IL-6 in the CHF lung. IL-6 peptide was also present in the pleural effusion of decompensated heart failure and was positively correlated with IL-6 mRNA expression in the lungs of decompensated HF rats. Pulmonary IL-6 overexpression was associated with nuclear translocation of NF-kappaB and cytosolic degradation of IkappaB.Conclusion: Dysfunctional pulmonary endothelium is a source of synthesis and storage of IL-6 in an experimental model of CHF. [ABSTRACT FROM AUTHOR]

Objectives: Endothelin-1 (ET-1), plays an important role in the pathophysiology of CHF and the pulmonary endothelium is an early hemodynamic target in diastolic left ventricular dysfunction. Therefore we hypothesized that the lung is a main source of humoral endothelin in CHF and that its secretion is proportional to the degree of heart failure. Methods and results: We used rats with coronary artery ligation as an experimental model of either compensated or decompensated heart failure, depending on infarct size. Reverse transcriptase polymerase chain reaction (RT-PCR) revealed that in the lung, the expression of preproET-1 mRNA was higher in decompensated HF than in control and compensated HF rats (P<0.001). Run-on assay demonstrated that ET-1 overexpression is regulated at a transcriptional level (P<0.01). In contrast, there was no change in ET-1 mRNA expression in aortae, left ventricular myocardium and skeletal muscle. The expression of endothelin-converting enzyme (ECE)-1 mRNA was not modified and the expression of ETB receptor mRNA in the congestive lung was significantly lower than in control and compensated HF rats (P<0.0001), while the expression of ETA receptor mRNA did not differ between groups. The lung and plasma ET-1 peptide levels were respectively 4.2 and 9 fold higher in the rats with decompensated HF than in control rats (P<0.05; P<0.0001). Organoculture experiments showed that the lung ET-1 peptide secretion level in rats with decompensated HF was higher than that in control rats (P<0.01). In contrast, there was no change in ET-1 peptide secretion by the left ventricular myocardium and skeletal muscle. In plasma of rats with decompensated HF, the rate of bigET-1 conversion to ET-1 was 22%. ET-1 peptide was also present in the pleural effusion of decompensated heart failure. Plasma ET-1 concentration was significantly correlated with upstream markers of left ventricular diastolic dysfunction, with the expression of preproET-1 mRNA in the lung, with lung and pleural ET-1 concentration and with the expression ratio of ET-1/ETB receptor mRNA. Conclusion: Taken together, these data suggest that overexpression of ET-1 and down-regulation of ETB receptors in the lung are determinants of circulating endothelin in CHF. As a corollary, increased plasma endothelin may provide evidence of pulmonary endothelial dysfunction in CHF. [ABSTRACT FROM PUBLISHER]

Presents a study which focused on thrombin to stimulate endothelin release by endothelial cells. Materials and methods; Results; Discussion of the results.

Characterizes the fourth isoform of endothelin-converting enzyme (ECE-1). Patterns of subcellular localization; Existence of additional promoter located upstream from the third exon of the ECE-1.

Percutaneous catheter valvuloplasty was performed in 37 patients between 60–88 years of age (mean age 74.5 years): 16 of these patients were in functional class IV, with pulmonary oedema at the time of the procedure. A good haemodynamic result was obtained in 32 patients, but 3 of them had to be operated upon subsequently, because of persistence of their symptoms. Two successfully dilated patients died in the hospital, one of cardiac failure following myocardial dysfunction caused by multiple infarcts which had no relation to the aortic dilatation, the other of neurological complications after dilatation. Thus, the primary success rate was 27/37 (73%). The first 10 patients with good initial results have been followed up for more than 6 months. The functional result has been maintained in 8 cases with moderate myocardial dysfunction (left ventricular ejection fraction 0.41 to 0.7), one with restenosis at Doppler assessment. Two patients with severe myocardial dysfunction (left ventricular ejection fraction 0.22 and 0.25) had recurrent cardiac failure, with valvular restenosis in one case. One of them died at home. Percutaneous aortic valvuloplasty is therefore an effective means of treating calcified aortic stenosis in elderly patients. The benefits of this procedure have been maintained for as long as 6 months provided myocardial dysfunction was moderate. At its present stage of development, the technique allows only partial reduction of the aortic stenosis, which may explain the absence of long-term improvement in patients with severe myocardial disease. [ABSTRACT FROM PUBLISHER]