Recursive Partitioning for the Prediction of Cytochromes P450 2D6 and 1A2 Inhibition:  Importance of the Quality of the Dataset

Abstract

The purpose of this study was to explore the use of detailed biological data in combination with a statistical learning method for predicting the CYP1A2 and CYP2D6 inhibition. Data were extracted from the Aureus-Pharma highly structured databases which contain precise measures and detailed experimental protocol concerning the inhibition of the two cytochromes. The methodology used was Recursive Partitioning, an easy and quick method to implement. The building of models was preceded by the evaluation of the chemical space covered by the datasets. The descriptors used are available in the MOE software suite. The models reached at least 80% of Accuracy and often exceeded this percentage for the Sensitivity (Recall), Specificity, and Precision parameters. CYP2D6 datasets provided 11 models with Accuracy over 80%, while CYP1A2 datasets counted 5 high-accuracy models. Our models can be useful to predict the ADME properties during the drug discovery process and are indicated for high-throughput screening.

Applicability of QSAR analysis to the evaluation of the toxicological relevance of metabolites and degradates of pesticide active substances for dietary risk assessment

“…An example of a model for CYP inhibition was proposed by Burton et al (2006), who constructed classification models for human CYP1A2 and CYP2D6 inhibition using binary decision trees. The modelling was based on 498 and 306 inhibition measures (IC50 and Ki values) for CYP1A2 and CYP2D6, respectively, collected from the Aureus Pharma (http://www.aureus-pharma.com/).…”

In SilicoADME/Tox Predictions

“…CYP2C9 tend to interact with amphipathic molecules and favor acidic compounds like some nonsteroidal anti-inflammatory agents. Numerous computer studies have been performed on diverse CYP enzymes using small datasets of compounds [17,145,193]. Several in silico packages and databases to predict CYP metabolism are listed in Table 2.8.…”

“…For toxicity properties, DTs are used to predict hERG inhibition [202] and toxicity involving cytochrome P450 such as six CYP isoforms [331], 2D6 and 1A2 isoforms [193,312], or the 3A4 isoform [332].…”

Untitled

“…Cytochrome P450 is the main enzyme involved in the oxidative metabolic pathways of many drugs 1 . In many cases inhibition of CYP leads to undesired growth of the administered therapeutic agent.…”