Anti- Toxoplasma Activities of 24 Quinolones and Fluoroquinolones In Vitro: Prediction of Activity by Molecular Topology and Virtual Computational Techniques

ABSTRACT The apicoplast, a plastid-like organelle of Toxoplasma gondii , is thought to be a unique drug target for quinolones. In this study, we assessed the in vitro activity of quinolones against T. gondii and developed new quantitative structure-activity relationship models able to predict this activity. The anti- Toxoplasma activities of 24 quinolones were examined by means of linear discriminant analysis (LDA) using topological indices as structural descriptors. In parallel, in vitro 50% inhibitory concentrations (IC 50 s) were determined in tissue culture. A multilinear regression (MLR) analysis was then performed to establish a model capable of classifying quinolones by in vitro acti…

Recent Advances in Computational Approaches for Designing Potential Anti-Alzheimer’s Agents

Prediction of chromatographic properties of organophosphorus insecticides by molecular connectivity

A study is reported of the relationship between theR F values for a group of organophosphorus insecticides obtained by thin layer chromatography and a series of topological descriptors. By using multivariate regression, the corresponding connectivity functions were obtained, which had been selected on the basis of their respective statistical parameters: multiple correlation coefficient (r), standard error of estimate (s), F-Snedecor values and statistical significance (Student’s t). Regression analysis of the connectivity functions can predict the elution behaviour of any structurally similar derivative of this group of compounds with different stationary and mobile phases. Stability studi…

Predictive modeling of aryl hydrocarbon receptor (AhR) agonism

Abstract The aryl hydrocarbon receptor (AhR) plays a key role in the regulation of gene expression in metabolic machinery and detoxification systems. In the recent years, this receptor has attracted interest as a therapeutic target for immunological, oncogenic and inflammatory conditions. In the present report, in silico and in vitro approaches were combined to study the activation of the AhR. To this end, a large database of chemical compounds with known AhR agonistic activity was employed to build 5 classifiers based on the Adaboost (AdB), Gradient Boosting (GB), Random Forest (RF), Multilayer Perceptron (MLP) and Support Vector Machine (SVM) algorithms, respectively. The built classifier…

Computational Evaluation and In Vitro Validation of New Epidermal Growth Factor Receptor Inhibitors

Background:The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein that acts as a receptor of extracellular protein ligands of the epidermal growth factor (EGF/ErbB) family. It has been shown that EGFR is overexpressed by many tumours and correlates with poor prognosis. Therefore, EGFR can be considered as a very interesting therapeutic target for the treatment of a large variety of cancers such as lung, ovarian, endometrial, gastric, bladder and breast cancers, cervical adenocarcinoma, malignant melanoma and glioblastoma.Methods:We have followed a structure-based virtual screening (SBVS) procedure with a library composed of several commercial collections of chemicals (615,46…

Applications of Chemoinformatics in Predictive Toxicology for Regulatory Purposes, Especially in the Context of the EU REACH Legislation

Chemoinformatics methodologies such as QSAR/QSPR have been used for decades in drug discovery projects, especially for the finding of new compounds with therapeutic properties and the optimization of ADME properties on chemical series. The application of computational techniques in predictive toxicology is much more recent, and they are experiencing an increasingly interest because of the new legal requirements imposed by national and international regulations. In the pharmaceutical field, the US Food and Drug Administration (FDA) support the use of predictive models for regulatory decision-making when assessing the genotoxic and carcinogenic potential of drug impurities. In Europe, the REA…

Safer chemicals using less animals: kick-off of the European ONTOX project

The 3Rs concept, calling for replacement, reduction and refinement of animal experimentation, is receiving increasing attention around the world, and has found its way to legislation, in particular in the European Union. This is aligned by continuing high-level efforts of the European Commission to support development and implementation of 3Rs methods. In this respect, the European project called "ONTOX: ontology-driven and artificial intelligence-based repeated dose toxicity testing of chemicals for next generation risk assessment" was recently initiated with the goal to provide a functional and sustainable solution for advancing human risk assessment of chemicals without the use of animal…

Elucidating the aryl hydrocarbon receptor antagonism from a chemical-structural perspective.

The aryl hydrocarbon receptor (AhR) plays an important role in several biological processes such as reproduction, immunity and homoeostasis. However, little is known on the chemical-structural and physicochemical features that influence the activity of AhR antagonistic modulators. In the present report, in vitro AhR antagonistic activity evaluations, based on a chemical-activated luciferase gene expression (AhR-CALUX) bioassay, and an extensive literature review were performed with the aim of constructing a structurally diverse database of contaminants and potentially toxic chemicals. Subsequently, QSAR models based on Linear Discriminant Analysis and Logistic Regression, as well as two tox…

Targeting the aryl hydrocarbon receptor with a novel set of triarylmethanes

International audience; The aryl hydrocarbon receptor (AhR) is a chemical sensor upregulating the transcription of responsive genes associated with endocrine homeostasis, oxidative balance and diverse metabolic, immunological and inflammatory processes, which have raised the pharmacological interest on its modulation. Herein, a novel set of 32 unsymmetrical triarylmethane (TAM) class of structures has been synthesized, characterized and their AhR transcriptional activity evaluated using a cell-based assay. Eight of the assayed TAM compounds (14, 15, 18, 19, 21, 22, 25, 28) exhibited AhR agonism but none of them showed antagonist effects. TAMs bearing benzotrifluoride, naphthol or heteroarom…

Application de la topologie moléculaire à la prédiction de la viscosité liquide des composés organiques

Nous avons applique la topologie moleculaire a la recherche d'un modele mathematique capable de predire la viscosite liquide d'un large groupe de composes organiques contenant C, H, O, N, S et des halogenes. Les descripteurs topologiques utilises pour cette etude des relations quantitatives structure-propiete, R.Q.S.P., sont les indices de connectivite de Kier et Hall -jusqu'a l'ordre quatre- ainsi que les indices atomiques electrotopologiques. La qualite de l'equation de regression multilineaire obtenue (aussi dite « fonction de connectivite») a ete evaluee par une etude de validation croisee. Tous les composes excepte le 1,1,2-trichlorotrifluorethane s'ajustent au modele propose.

Prediction of quinolone activity against Mycobacterium avium by molecular topology and virtual computational screening.

ABSTRACT We conducted a quantitative structure-activity relationship study using a database of 158 quinolones previously tested against Mycobacterium avium-M. intracellulare complex in order to develop a model capable of predicting the activity of new quinolones against the M. avium-M. intracellulare complex in vitro. Topological indices were used as structural descriptors and were related to anti- M. avium-M. intracellulare complex activity by using the linear discriminant analysis (LDA) statistical technique. The discriminant equation thus obtained correctly classified 137 of the 158 quinolones, including 37 of a test group of 44 randomly chosen compounds. This model was then applied to 2…

Use of molecular topology for the prediction of physico-chemical, pharmacokinetic and toxicological properties of a group of antihistaminic drugs

We used molecular connectivity to search mathematical models for predicting physico-chemical (e.g. the partition coefficient, P), pharmacokinetic (e.g. the time of maximum plasma level, and toxicological properties (lethal dose, LD) for a group of antihistaminic drugs. The results obtained clearly reveal the high efficiency of molecular topology for the prediction of these properties. Randomization and cross-validation by use of leave-one-out tests were also performed in order to assess the stability and the prediction ability of the connectivity functions selected.