title: Development of a new predictive model for interactions with human cytochrome P450 2A6 using pharmacophore ensemble/support vector machine (PhE/SVM) approach.
abstract: OBJECTIVE
  The objective of this investigation was to yield a generalized in silico model to quantitatively predict CYP2A6-substrates/inhibitors interactions to facilitate drug discovery.
  
  
  METHODS
  The newly invented pharmacophore ensemble/support vector machine (PhE/SVM) scheme was employed to generate the prediction model based on the data compiled from the literature.
  
  
  RESULTS
  The predictions by the PhE/SVM model are in good agreement with the experimental observations for those molecules in the training set (n = 24, r (2) = 0.94, q (2) = 0.85, RMSE = 0.30) and the test set (n = 9, r (2) = 0.96, RMSE = 0.29). In addition, this in silico model performed equally well for those molecules in the external validation sets, namely one set of benzene and naphthalene derivatives (n = 45, r (2) = 0.81, RMSE = 0.46) and one set of amine neurotransmitters (n = 4, r (2) = 0.98, RMSE = 0.32). Furthermore, when compared with crystal structures, the calculated results are consistent with the published CYP2A6-substrate co-complex structure and the plasticity nature of CYP2A6 is also revealed.
  
  
  CONCLUSIONS
  This PhE/SVM model is an accurate and robust model and can be utilized for predicting interactions with CYP2A6, high-throughput screening and data mining to facilitate drug discovery.
authors.affiliation: Department of Chemistry, National Dong Hwa University, Shoufeng, Hualien, 97401, Taiwan. leong@mail.ndhu.edu.tw
authors.forename: Max K
authors.initials: MK
authors.lastname: Leong
authors.forename: Yen-Ming
authors.initials: YM
authors.lastname: Chen
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Chen
authors.forename: Po-Hong
authors.initials: PH
authors.lastname: Chen
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D017076:Computer-Aided Design; D065637:Cytochrome P-450 CYP2A6; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6