title: Improved Prediction of Michaelis Constants in CYP450-Mediated Reactions by Resilient Back Propagation Algorithm.
abstract: BACKGROUND
  In drug metabolism reactions, it has become increasingly important to measure Michaelis constants (Km), which are used for a variety of purposes, including identification of enzymes involved in drug metabolism, prediction of drug-drug interactions, etc. Cytochrome P450s (CYPs) comprise a super family of major human enzymes responsible for drug metabolism. Hence, computational prediction of Km in CYP-mediated reactions facilitates drug development in an efficient and economical way.
  
  
  METHODS
  In this study, we firstly constructed a large dataset of ten CYP isoforms associated with 169 binding substrates, and 210 experimental Km values in CYP-mediated reactions. To predict Km of substrates metabolized by various CYP isoforms, we developed a general prediction model by using resilient back-propagation neutral network algorithm, based on the structural and physicochemical properties of the substrates and the metabolic specificity of the enzymes.
  
  
  RESULTS
  The predictive Km values achieve a squared cross-validation correlation coefficients (Q2) of 0.73 with the experimental values, which is better than that of the existing models. Moreover, our model can predict Kmvalues of the compounds metabolized by a wide range of CYP isoforms.
  
  
  CONCLUSIONS
  This tool will be useful in large-scale drug screening studies for CYP enzymes and helpful in the drug design and development.
authors.forename: Hao
authors.initials: H
authors.lastname: Dai
authors.affiliation: Room 4-321, Life Science Building, Shanghai Jiaotong University, 800 Dongchuan Road, 200240, Minhang District, Shanghai, China. xuqin523@sjtu.edu.cn.
authors.forename: Qin
authors.initials: Q
authors.lastname: Xu
authors.forename: Yi
authors.initials: Y
authors.lastname: Xiong
authors.forename: Wei-Lin
authors.initials: WL
authors.lastname: Liu
authors.forename: Dong-Qing
authors.initials: DQ
authors.lastname: Wei
mesh_terms: D000465:Algorithms; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism
chemical_list: D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System