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Development of a Simplified in Vitro P-glycoprotein Substrate Assay and in Silico Prediction Models to Evaluate Transport Potential of P-glycoprotein.

08:00 EDT 1st April 2019 | BioPortfolio

Summary of "Development of a Simplified in Vitro P-glycoprotein Substrate Assay and in Silico Prediction Models to Evaluate Transport Potential of P-glycoprotein."

For efficient drug discovery and screening, it is necessary to simplify P-glycoprotein (P-gp) substrate assays and to provide in silico models that predict the transport potential of P-gp. In this study, we developed a simplified in vitro screening method to evaluate P-gp substrates by unidirectional membrane transport in P-gp-overexpressing cells. The unidirectional flux ratio positively correlated with parameters of the conventional bidirectional P-gp substrate assay (R2 = 0.941) and in vivo Kp, brain ratio (mdr1a/b KO/WT) in mice (R2 = 0.800). Our in vitro P-gp substrate assay had high reproducibility and required approximately half the labor of the conventional method. We also constructed regression models to predict the value of P-gp-mediated flux and three-class classification models to predict P-gp substrate potential (low-, medium-, and high-potential) using 2397 data entries with the largest dataset collected under the same experimental conditions. Most compounds in the test set fell within 2- and 3-fold errors in the random forest regression model (71.3 and 88.5%, respectively). Furthermore, the random forest three-class classification model showed a high balanced accuracy of 0.821 and precision of 0.761 for the low-potential classes in the test set. We concluded that the simplified in vitro P-gp substrate assay was suitable for compound screening in the early stages of drug discovery and the in silico regression model and three-class classification model using only chemical structure information could identify the transport potential of compounds including P-gp-mediated flux ratios. Our proposed method is expected to be a practical tool to optimize effective central nervous system (CNS) drugs, to avoid CNS side effects, and to improve intestinal absorption.

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This article was published in the following journal.

Name: Molecular pharmaceutics
ISSN: 1543-8392
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