Naslov
Accurate Models for P-gp Drug Recognition Induced from a Cancer Cell Line Cytotoxicity Screen

Autori
Levatić, Jurica ; Ćurak, Jasna ; Kralj, Marijeta ; Šmuc, Tomislav ; Osmak, Maja ; Supek, Fran

Izvornik
Journal of medicinal chemistry (0022-2623) 56 (2013), 14; 5691-5708

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
P-gp ; ABCB1 ; drug efflux ; cell line screen ; chemoterapy resistance

Sažetak
P-glycoprotein (P-gp, MDR1) is a promiscuous drug efflux pump of substantial pharmacological importance. Taking advantage of large-scale cytotoxicity screening data involving 60 cancer cell lines, we correlated the differential biological activities of 13 000 compounds against cellular P-gp levels. We created a large set of 934 high-confidence P-gp substrates or nonsubstrates by enforcing agreement with an orthogonal criterion involving P-gp overexpressing ADR-RES cells. A support vector machine (SVM) was 86.7% accurate in discriminating P-gp substrates on independent test data, exceeding previous models. Two molecular features had an overarching influence: nearly all P-gp substrates were large (>35 atoms including H) and dense (specific volume of <7.3 Å3/atom) molecules. Seven other descriptors and 24 molecular fragments (“effluxophores”) were found enriched in the (non)substrates and incorporated into interpretable rule-based models. Biological experiments on an independent P-gp overexpressing cell line, the vincristine-resistant VK2, allowed us to reclassify six compounds previously annotated as substrates, validating our method’s predictive ability. Models are freely available at http://pgp.biozyne.com.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Računarstvo, Temeljne medicinske znanosti

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