title: Prediction of cytochrome P450 isoform responsible for metabolizing a drug molecule.
abstract: BACKGROUND
  Different 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).
  
  
  RESULTS
  All 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%.
  
  
  CONCLUSIONS
  This 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/.
authors.affiliation: Bioinformatics Centre, Institute of Microbial Technology, Chandigarh, India.
authors.forename: Nitish K
authors.initials: NK
authors.lastname: Mishra
authors.forename: Sandhya
authors.initials: S
authors.lastname: Agarwal
authors.forename: Gajendra Ps
authors.initials: GP
authors.lastname: Raghava
mesh_terms: D000465:Algorithms; D001185:Artificial Intelligence; D019295:Computational Biology / Q000379:methods*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D016208:Databases, Factual; D005103:Expert Systems; D020407:Internet; D007527:Isoenzymes / Q000378:metabolism; D050216:Metabolic Detoxication, Phase I; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D012984:Software; D013379:Substrate Specificity
chemical_list: D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System