Prediction of cytochrome P450 isoform responsible for metabolizing a drug molecule

Abstract

BackgroundDifferent isoforms of Cytochrome P450 (CYP) metabolized different types of substrates (or drugs molecule) and make them soluble during biotransformation. Therefore, fate of any drug molecule depends on how they are treated or metabolized by CYP isoform. There is a need to develop models for predicting substrate specificity of major isoforms of P450, in order to understand whether a given drug will be metabolized or not. This paper describes an in-silico method for predicting the metabolizing capability of major isoforms (e.g. CYP 3A4, 2D6, 1A2, 2C9 and 2C19).ResultsAll models were trained and tested on 226 approved drug molecules. Firstly, 2392 molecular descriptors for each drug molecule were calculated using various softwares. Secondly, best 41 descriptors were selected using general and genetic algorithm. Thirdly, Support Vector Machine (SVM) based QSAR models were developed using 41 best descriptors and achieved an average accuracy of 86.02%, evaluated using fivefold cross-validation. We have also evaluated the performance of our model on an independent dataset of 146 drug molecules and achieved average accuracy 70.55%. In addition, SVM based models were developed using 26 Chemistry Development Kit (CDK) molecular descriptors and achieved an average accuracy of 86.60%.ConclusionsThis study demonstrates that SVM based QSAR model can predict substrate specificity of major CYP isoforms with high accuracy. These models can be used to predict isoform responsible for metabolizing a drug molecule. Thus these models can used to understand whether a molecule will be metabolized or not. This is possible to develop highly accurate models for predicting substrate specificity of major isoforms using CDK descriptors. A web server MetaPred has been developed for predicting metabolizing isoform of a drug molecule http://crdd.osdd.net/raghava/metapred/.

Pharmacokinetics of reduced iso-α-acids in volunteers following clear bottled beer consumption

“…Furthermore, Cattoor et al examines the probable sights of metabolism for the RIAA and TIAA in detail and suggests phase I (IAA and TIAA) and phase II (RIAA) processes [7]. Additional pharmacokinetic information can be obtained with use of the in silico metabolism pathway prediction modelling software which suggested that the CYP2C9 was primarily responsible for the oxidation of the reduced IAA compounds [32]. Furthermore, a CYPmediated metabolism prediction tool proposed the most probable sites of metabolism occurred at the end of both side chains on the four methyl groups for reduced IAA groups [33].…”

Forensic Pharmacogenetics

“…Moreover, the phenomenon of phenocopying must be taken into account where EM individuals turn into apparent PM or IM phenotypes because of drug-drug interactions (Owen et al, 2009). Many drugs also inhibit or induce the activity of CYPs and knowledge of CYP-drug relations is therefore essential to recognize incompatible drug combinations and allows individualized therapies (Mishra et al, 2010). For this purpose, a user-friendly platform for researchers and health professionals was developed where each drug was attributed to those CYPs involved in drug metabolism as substrate, inhibitor or inducer.…”

Precursors for cytochrome P450 profiling breath tests from an in silico screening approach

“…Another systematical drawback of a decision tree model is the defiance in considering multiple isoforms often involved in the metabolism of a single molecule. Mishra et al propose a multi-label prediction relying on support vector machine models for five implemented CYP isoforms [60]. The training data of this publication was also extracted from the DrugBank.…”