title: A novel chemometric method for the prediction of human oral bioavailability.
abstract: Orally administered drugs must overcome several barriers before reaching their target site. Such barriers depend largely upon specific membrane transport systems and intracellular drug-metabolizing enzymes. For the first time, the P-glycoprotein (P-gp) and cytochrome P450s, the main line of defense by limiting the oral bioavailability (OB) of drugs, were brought into construction of QSAR modeling for human OB based on 805 structurally diverse drug and drug-like molecules. The linear (multiple linear regression: MLR, and partial least squares regression: PLS) and nonlinear (support-vector machine regression: SVR) methods are used to construct the models with their predictivity verified with five-fold cross-validation and independent external tests. The performance of SVR is slightly better than that of MLR and PLS, as indicated by its determination coefficient (R(2)) of 0.80 and standard error of estimate (SEE) of 0.31 for test sets. For the MLR and PLS, they are relatively weak, showing prediction abilities of 0.60 and 0.64 for the training set with SEE of 0.40 and 0.31, respectively. Our study indicates that the MLR, PLS and SVR-based in silico models have good potential in facilitating the prediction of oral bioavailability and can be applied in future drug design.
authors: College of Science, Northwest A & F University, Yangling 712100, China.|College of Life Science, Northwest A & F University, Yangling 712100, China.
authors: Xue
authors: X
authors: Xu
authors: College of Science, Northwest A & F University, Yangling 712100, China.
authors: Wuxia
authors: W
authors: Zhang
authors: College of Life Science, Northwest A & F University, Yangling 712100, China.
authors: Chao
authors: C
authors: Huang
authors: School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China.
authors: Yan
authors: Y
authors: Li
authors: College of Life Science, Northwest A & F University, Yangling 712100, China.
authors: Hua
authors: H
authors: Yu
authors: College of Life Science, Northwest A & F University, Yangling 712100, China.
authors: Yonghua
authors: Y
authors: Wang
authors: College of Science, Northwest A & F University, Yangling 712100, China.
authors: Jinyou
authors: J
authors: Duan
authors: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors: Yang
authors: Y
authors: Ling
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry; D000284:Administration, Oral; D001682:Biological Availability; D016000:Cluster Analysis; D019295:Computational Biology; D018360:Crystallography, X-Ray; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry; D016208:Databases, Factual; D015195:Drug Design; D006801:Humans; D016014:Linear Models; D008968:Molecular Conformation; D016571:Neural Networks, Computer; D021281:Quantitative Structure-Activity Relationship; D060388:Support Vector Machine
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A