title: Critical evaluation of human oral bioavailability for pharmaceutical drugs by using various cheminformatics approaches.
abstract: OBJECTIVE
  Oral bioavailability (%F) is a key factor that determines the fate of a new drug in clinical trials. Traditionally, %F is measured using costly and time-consuming experimental tests. Developing computational models to evaluate the %F of new drugs before they are synthesized would be beneficial in the drug discovery process.
  
  
  METHODS
  We employed Combinatorial Quantitative Structure-Activity Relationship approach to develop several computational %F models. We compiled a %F dataset of 995 drugs from public sources. After generating chemical descriptors for each compound, we used random forest, support vector machine, k nearest neighbor, and CASE Ultra to develop the relevant QSAR models. The resulting models were validated using five-fold cross-validation.
  
  
  RESULTS
  The external predictivity of %F values was poor (R(2) = 0.28, n = 995, MAE = 24), but was improved (R(2) = 0.40, n = 362, MAE = 21) by filtering unreliable predictions that had a high probability of interacting with MDR1 and MRP2 transporters. Furthermore, classifying the compounds according to the %F values (%F < 50% as "low", %F ≥ 50% as 'high") and developing category QSAR models resulted in an external accuracy of 76%.
  
  
  CONCLUSIONS
  In this study, we developed predictive %F QSAR models that could be used to evaluate new drug compounds, and integrating drug-transporter interactions data greatly benefits the resulting models.
authors.affiliation: Department of Chemistry, Rutgers University, Camden, New Jersey, 08102, USA.
authors.forename: Marlene T
authors.initials: MT
authors.lastname: Kim
authors.forename: Alexander
authors.initials: A
authors.lastname: Sedykh
authors.forename: Suman K
authors.initials: SK
authors.lastname: Chakravarti
authors.forename: Roustem D
authors.initials: RD
authors.lastname: Saiakhov
authors.forename: Hao
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods / Q000592:standards*; D016208:Databases, Factual; D006801:Humans; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004364:Pharmaceutical Preparations