Development of Classification Models for Identifying “True” P-glycoprotein (P-gp) Inhibitors Through Inhibition, ATPase Activation and Monolayer Efflux Assays

International Journal of Molecular Sciences

Simona Rapposelli¹  Alessio Coi²  Marcello Imbriani³ 

[1] Department of Pharmaceutical Sciences, University of Pisa, Via Bonanno 6, Pisa 56126, Italy; E-Mail:;Consorzio Interuniversitario Nazionale per la Scienza e la Tecnologia dei Materiali (INSTM), Via Giusti 9, Firenze 50121, Italy; E-Mail:;Fondazione S. Maugeri, Via S. Maugeri 4, Pavia 27100, Italy; E-Mail:

关键词: P-glicoprotein;    decision trees;    classification model;    consensus model;    P-gp inhibitors;    MDR1 ligands;   

DOI  :  10.3390/ijms13066924

来源: mdpi

【 摘 要 】

P-glycoprotein (P-gp) is an efflux pump involved in the protection of tissues of several organs by influencing xenobiotic disposition. P-gp plays a key role in multidrug resistance and in the progression of many neurodegenerative diseases. The development of new and more effective therapeutics targeting P-gp thus represents an intriguing challenge in drug discovery. P-gp inhibition may be considered as a valid approach to improve drug bioavailability as well as to overcome drug resistance to many kinds of tumours characterized by the over-expression of this protein. This study aims to develop classification models from a unique dataset of 59 compounds for which there were homogeneous experimental data on P-gp inhibition, ATPase activation and monolayer efflux. For each experiment, the dataset was split into a training and a test set comprising 39 and 20 molecules, respectively. Rational splitting was accomplished using a sphere-exclusion type algorithm. After a two-step (internal/external) validation, the best-performing classification models were used in a consensus predicting task for the identification of compounds named as “true” P-gp inhibitors, i.e., molecules able to inhibit P-gp without being effluxed by P-gp itself and simultaneously unable to activate the ATPase function.

【 授权许可】

CC BY   
© 2012 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.