ADME Evaluation in Drug Discovery.10.Predictions of P-Glycoprotein Inhibitors Using Recursive Partitioning and Naive Bayesian Classification Techniques
P-Glycoprotein (P-gp),an efflux transporter,plays a crucial role in drug pharmacokinetic properties (ADME),and is critical for multidmg resistance (MDR) by mediating the active transport of anticancer drugs from the intracellular to the extracellular compartment.Here we reported an original database of 1273 molecules that are categorized into P-gp inhibitors and noninhibitors.The impact of various physicochemical properties on P-gp inhibition was examined.We then built the decision trees from a training set of 973 compounds using the recursive partitioning (RP) technique and validated by an external test set of 300 compounds.The best decision tree correctly predicted 83.596 of the inhibitors and 67.09% of the noninhibitors in the test set.Finally,we applied naiveBayesian categorization modeling to establish classifiers for P-gp inhibitors.The Bayesian classifier gave average correct prediction for 81.7% of 973 compounds in the training set with leave-one-out cross-validation procedure and 81.2% of 300 compounds in the test set.By establishing multiple decision trees and Bayesian classifiers,we evaluated the impact of molecular fingerprints on classification by the prediction accuracy for the test set,and we found that the inclusion of molecular fingerprints improves the prediction obviously.As an unsupervised learner without tuning parameters,the Bayesian classifier employing fingerprints highlights the important structural fragments favorable or unfavorable for P-gp transport,which provides critical information for designing new efficient P-gp inhibitors.
P-glycoprotein naive Bayesian classification recursive partitioning ADME/T ABCB1 ABC transporter multidrug resistance (MDR)
Lei Chen Youyong Li Qing Zhao Hui Peng Tingjun Hou
Institute of Functional Nano & Soft Materials(FUNSOM)and Jiangsu Key Laboratory for Carbon-Based Fun Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing 100850, China
国际会议
南京
英文
25-36
2012-05-13（万方平台首次上网日期，不代表论文的发表时间）