title: Computational prediction of CNS drug exposure based on a novel in vivo dataset.
abstract: OBJECTIVE
  To develop a computational model for predicting CNS drug exposure using a novel in vivo dataset.
  
  
  METHODS
  The brain-to-plasma (B:P) ratio of 43 diverse compounds was assessed following intravenous administration to Swiss Outbred mice. B:P ratios were subjected to PLS modeling using calculated molecular descriptors. The obtained results were transferred to a qualitative setting in which compounds predicted to have a B:P ratio > 0.3 were sorted as high CNS exposure compounds and those below this value were sorted as low CNS exposure compounds. The model was challenged with an external test set consisting of 251 compounds for which semi-quantitative values of CNS exposure were available in the literature.
  
  
  RESULTS
  The dataset ranged more than 1700-fold in B:P ratio, with 16 and 27 compounds being sorted as low and high CNS exposure drugs, respectively. The model was a one principal component model based on five descriptors reflecting molecular shape, electronegativity, polarisability and charge transfer, and allowed 74% of the compounds in the training set and 76% of the test set to be predicted correctly.
  
  
  CONCLUSIONS
  A qualitative computational model has been developed which accurately classifies compounds as being high or low CNS exposure drugs based on rapidly calculated molecular descriptors.
authors: Department of Pharmacy Drug Optimization and Pharmaceutical Profiling Platform, Uppsala University, Uppsala Biomedical Center, P.O. Box 580, SE-751 23, Uppsala, Sweden.
authors: Christel A S
authors: CA
authors: Bergström
authors: Susan A
authors: SA
authors: Charman
authors: Joseph A
authors: JA
authors: Nicolazzo
mesh_terms: D061605:Administration, Intravenous / Q000379:methods; D000818:Animals; D021461:Animals, Outbred Strains; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D003198:Computer Simulation; D051379:Mice; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000097:blood / Q000378:metabolism*; D010599:Pharmacokinetics
chemical_list: D002491:Central Nervous System Agents; D004364:Pharmaceutical Preparations