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Int. J. Mol. Sci. 2012, 13(6), 6924-6943; doi:10.3390/ijms13066924
Article

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

1
, 2
, 3
 and 1,4,*
Received: 22 March 2012; in revised form: 21 May 2012 / Accepted: 31 May 2012 / Published: 7 June 2012
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Abstract: 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.
Keywords: P-glicoprotein; decision trees; classification model; consensus model; P-gp inhibitors; MDR1 ligands P-glicoprotein; decision trees; classification model; consensus model; P-gp inhibitors; MDR1 ligands
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Rapposelli, S.; Coi, A.; Imbriani, M.; Bianucci, A.M. Development of Classification Models for Identifying “True” P-glycoprotein (P-gp) Inhibitors Through Inhibition, ATPase Activation and Monolayer Efflux Assays. Int. J. Mol. Sci. 2012, 13, 6924-6943.

AMA Style

Rapposelli S, Coi A, Imbriani M, Bianucci AM. 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. 2012; 13(6):6924-6943.

Chicago/Turabian Style

Rapposelli, Simona; Coi, Alessio; Imbriani, Marcello; Bianucci, Anna Maria. 2012. "Development of Classification Models for Identifying “True” P-glycoprotein (P-gp) Inhibitors Through Inhibition, ATPase Activation and Monolayer Efflux Assays." Int. J. Mol. Sci. 13, no. 6: 6924-6943.


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