Méthodologie générale d’une étude ACP : Généralités, concepts et exemples

Le développement des modèles statistiques des relations quantitatives structure-activité/propriété joue un rôle important dans la conception de nouveaux produits chimiques spécialement pharmaceutiques. La prédiction des propriétés biologiques des produits non testées passe d’abord par une analyse ACP. Il s’agit de l’analyse en composante principale : c’est une méthode basée sur des statistiques descriptives multidimensionnelles permettant de traiter simultanément un nombre quelconque de variables quantitatives. L’objectif est de visualiser et résumer l’information contenue dans les différentes données afin d’avoir une représentation permettant plus facilement l’interprétation. Dans ce papier, nous décrivons des généralités et les principaux concepts et techniques les plus pertinents pour la réalisation d’une étude ACP

Bioluminescent kinase strips: A novel approach to targeted and flexible kinase inhibitor profiling

AbstractIn addition to target efficacy, drug safety is a major requirement during the drug discovery process and is influenced by target specificity. Therefore, it is imperative that every new drug candidate be profiled against various liability panels that include protein kinases. Here, an effective methodology to streamline kinase inhibitor profiling is described. An accessible standardized profiling system for 112 protein kinases covering all branches of the kinome was developed. This approach consists of creating different sets of kinases and their corresponding substrates in multi-tube strips. The kinase stocks are pre-standardized for optimal kinase activity and used for inhibitor profiling using a bioluminescent ADP detection assay. We show that these strips can routinely generate inhibitor selectivity profiles for small or broad kinase family panels. Lipid kinases were also assembled in strip format and profiled together with protein kinases. We identified two specific PI3K inhibitors that have off-target effects on CK2 that were not reported before and would have been missed if compounds were not profiled against lipid and protein kinases simultaneously. To validate the accuracy of the data generated by this method, we confirmed that the inhibition potencies observed are consistent with published values produced by more complex technologies such as radioactivity assays