University of Hertfordshire

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Original languageEnglish
Number of pages28
Pages (from-to)939-966
JournalSAR and QSAR in Environmental Research
Journal publication dateDec 2014
Volume25
Issue12
Early online date1 Dec 2014
DOIs
Publication statusPublished - Dec 2014

Abstract

P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) are two members of the adenosine triphosphate (ATP) binding cassette (ABC) family of transporters which function as membrane efflux transporters and display considerable substrate promiscuity. Both are known to significantly influence the absorption, distribution and elimination of drugs, mediate drug–drug interactions and contribute to multiple drug resistance (MDR) of cancer cells. Correspondingly, timely characterization of the interaction of novel leads and drug candidates with these two transporters is of great importance. In this study, several computational classification models for prediction of transport and inhibition of P-gp and BCRP, respectively, were developed based on newly compiled and critically evaluated experimental data. Artificial neural network (ANN) and support vector machine (SVM) ensemble based models were explored, as well as knowledge-based approaches to descriptor selection. The average overall classification accuracy of best performing models was 82% for P-gp transport, 88% for BCRP transport, 89% for P-gp inhibition and 87% for BCRP inhibition, determined across an array of different test sets. An analysis of substrate overlap between P-gp and BCRP was also performed. The accuracy, simplicity and interpretability of the proposed models suggest that they could be of significant utility in the drug discovery and development settings.

Notes

Date of Acceptance: 13/08/2014

ID: 7970574