title: Computational classification models for predicting the interaction of drugs with P-glycoprotein and breast cancer resistance protein.
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.
authors.affiliation: a Department of Pharmaceutical Chemistry , University of Belgrade , Belgrade , Serbia.
authors.forename: S
authors.initials: S
authors.lastname: Erić
authors.forename: M
authors.initials: M
authors.lastname: Kalinić
authors.forename: K
authors.initials: K
authors.lastname: Ilić
authors.forename: M
authors.initials: M
authors.lastname: Zloh
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism; D003198:Computer Simulation; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D006801:Humans; D008956:Models, Chemical; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D016571:Neural Networks, Computer; D021281:Quantitative Structure-Activity Relationship; D060388:Support Vector Machine
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins
keywords: P-glycoprotein; breast cancer resistance protein; classifier model; multiple drug resistance; prediction