title: Development of classification models for identifying "true" P-glycoprotein (P-gp) inhibitors through inhibition, ATPase activation and monolayer efflux assays.
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.
authors: Department of Pharmaceutical Sciences, University of Pisa, Via Bonanno 6, Pisa 56126, Italy.
authors: Simona
authors: 0000-0003-0146-6358
authors: S
authors: Rapposelli
authors: Consorzio Interuniversitario Nazionale per la Scienza e la Tecnologia dei Materiali (INSTM), Via Giusti 9, Firenze 50121, Italy.
authors: Alessio
authors: A
authors: Coi
authors: Fondazione S. Maugeri, Via S. Maugeri 4, Pavia 27100, Italy.
authors: Marcello
authors: M
authors: Imbriani
authors: Department of Pharmaceutical Sciences, University of Pisa, Via Bonanno 6, Pisa 56126, Italy.|International Centre for Studies and Research in Biomedicine (ICB) A.s.b.l., Luxembourg L-4947, Luxembourg.
authors: Anna Maria
authors: AM
authors: Bianucci
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000465:Algorithms; D019540:Area Under Curve; D019295:Computational Biology; D003663:Decision Trees; D015195:Drug Design; D004789:Enzyme Activation; D006801:Humans; D008024:Ligands; D015233:Models, Statistical; D010539:Permeability; D021381:Protein Transport; D015262:Xenobiotics / Q000737:chemistry
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D008024:Ligands; D015262:Xenobiotics; D000251:Adenosine Triphosphatases