title: A comparative analysis of protein targets of withdrawn cardiovascular drugs in human and mouse.
abstract: BACKGROUND
  Mouse is widely used in animal testing of cardiovascular disease. However, a large number of cardiovascular drugs that have been experimentally proved to work well on mouse were withdrawn because they caused adverse side effects in human.
  
  
  METHODS
  In this study, we investigate whether binding patterns of withdrawn cardiovascular drugs are conserved between mouse and human through computational dockings and molecular dynamic simulations. In addition, we also measured the level of conservation of gene expression patterns of the drug targets and their interacting partners by analyzing the microarray data.
  
  
  RESULTS
  The results show that target proteins of withdrawn cardiovascular drugs are functionally conserved between human and mouse. However, all the binding patterns of withdrawn drugs we retrieved show striking difference due to sequence divergence in drug-binding pocket, mainly through loss or gain of hydrogen bond donors and distinct drug-binding pockets. The binding affinities of withdrawn drugs to their receptors tend to be reduced from mouse to human. In contrast, the FDA-approved and best-selling drugs are little affected.
  
  
  CONCLUSIONS
  Our analysis suggests that sequence divergence in drug-binding pocket may be a reasonable explanation for the discrepancy of drug effects between animal models and human.
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, 32, Eastern Jiaochang Road, Kunming, Yunnan, 650223, China. huangjf@mail.kiz.ac.cn.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jingwen
authors.initials: J
authors.lastname: Wang
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Wang
authors.forename: Jingfei
authors.initials: J
authors.lastname: Huang