title: ADME Properties Evaluation in Drug Discovery: Prediction of Caco-2 Cell Permeability Using a Combination of NSGA-II and Boosting.
abstract: The Caco-2 cell monolayer model is a popular surrogate in predicting the in vitro human intestinal permeability of a drug due to its morphological and functional similarity with human enterocytes. A quantitative structure-property relationship (QSPR) study was carried out to predict Caco-2 cell permeability of a large data set consisting of 1272 compounds. Four different methods including multivariate linear regression (MLR), partial least-squares (PLS), support vector machine (SVM) regression and Boosting were employed to build prediction models with 30 molecular descriptors selected by nondominated sorting genetic algorithm-II (NSGA-II). The best Boosting model was obtained finally with R(2) = 0.97, RMSEF = 0.12, Q(2) = 0.83, RMSECV = 0.31 for the training set and RT(2) = 0.81, RMSET = 0.31 for the test set. A series of validation methods were used to assess the robustness and predictive ability of our model according to the OECD principles and then define its applicability domain. Compared with the reported QSAR/QSPR models about Caco-2 cell permeability, our model exhibits certain advantage in database size and prediction accuracy to some extent. Finally, we found that the polar volume, the hydrogen bond donor, the surface area and some other descriptors can influence the Caco-2 permeability to some extent. These results suggest that the proposed model is a good tool for predicting the permeability of drug candidates and to perform virtual screening in the early stage of drug development.
authors.affiliation: School of Pharmaceutical Sciences, Central South University , Changsha 410013, P. R. China.
authors.forename: Ning-Ning
authors.initials: NN
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Central South University , Changsha 410013, P. R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Dong
authors.affiliation: School of Pharmaceutical Sciences, Central South University , Changsha 410013, P. R. China.
authors.forename: Yin-Hua
authors.initials: YH
authors.lastname: Deng
authors.affiliation: School of Mathematics and Statistics, Central South University , Changsha 410083, P. R. China.
authors.forename: Min-Feng
authors.initials: MF
authors.lastname: Zhu
authors.affiliation: College of Chemistry and Chemical Engineering, Central South University , Changsha 410083, P. R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Wen
authors.affiliation: School of Pharmaceutical Sciences, Central South University , Changsha 410013, P. R. China.|College of Chemistry and Chemical Engineering, Central South University , Changsha 410083, P. R. China.
authors.forename: Zhi-Jiang
authors.initials: ZJ
authors.lastname: Yao
authors.affiliation: Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University , Hong Kong SAR, P. R. China.
authors.forename: Ai-Ping
authors.initials: AP
authors.lastname: Lu
authors.affiliation: College of Chemistry and Chemical Engineering, Central South University , Changsha 410083, P. R. China.
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Central South University , Changsha 410013, P. R. China.|Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University , Hong Kong SAR, P. R. China.
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Cao
mesh_terms: D065966:Absorption, Physicochemical; D001682:Biological Availability; D018938:Caco-2 Cells; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D010539:Permeability; D021281:Quantitative Structure-Activity Relationship