A Novel Chemometric Method for the Prediction of Human Oral Bioavailability
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Open Access
- 6 June 2012
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 13 (6), 6964-6982
- https://doi.org/10.3390/ijms13066964
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 (R2) 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.Keywords
This publication has 37 references indexed in Scilit:
- ADME Evaluation in Drug Discovery. 9. Prediction of Oral Bioavailability in Humans Based on Molecular Properties and Structural FingerprintsMolecular Pharmaceutics, 2011
- Quantitative structure–property relationship for surface tension of some common alcoholsJournal of Chemometrics, 2011
- Influence of P-glycoprotein on embryotoxicity of the antifouling biocides to sea urchin (Strongylocentrotus intermedius)Ecotoxicology, 2011
- Structure of P-Glycoprotein Reveals a Molecular Basis for Poly-Specific Drug BindingScience, 2009
- Explorations into modeling human oral bioavailabilityEuropean Journal of Medicinal Chemistry, 2008
- Augmented Three‐mode MIA‐QSAR Modeling for a Series of Anti‐HIV‐1 CompoundsQSAR & Combinatorial Science, 2008
- Prediction models of human plasma protein binding rate and oral bioavailability derived by using GA–CG–SVM methodJournal of Pharmaceutical and Biomedical Analysis, 2008
- Surflex: Fully Automatic Flexible Molecular Docking Using a Molecular Similarity-Based Search EngineJournal of Medicinal Chemistry, 2003
- The Mucosa of the Small IntestineClinical Pharmacokinetics, 2002
- Multivariate Determination of Glucose in Whole Blood Using Partial Least-Squares and Artificial Neural Networks Based on Mid-Infrared SpectroscopyApplied Spectroscopy, 1993