title: A novel approach for predicting P-glycoprotein (ABCB1) inhibition using molecular interaction fields.
abstract: P-glycoprotein (Pgp or ABCB1) is an ABC transporter protein involved in intestinal absorption, drug metabolism, and brain penetration, and its inhibition can seriously alter a drug's bioavailability and safety. In addition, inhibitors of Pgp can be used to overcome multidrug resistance. Given this dual purpose, reliable in silico procedures to predict Pgp inhibition are of great interest. A large and accurate literature collection yielded more than 1200 structures; a model was then constructed using various molecular interaction field-based technologies, considering pharmacophoric features and those physicochemical properties related to membrane partitioning. High accuracy was demonstrated internally with two different validation sets and, moreover, using a number of molecules, for which Pgp inhibition was not experimentally available but was evaluated in-house. All of the validations confirmed the robustness of the model and its suitability to help medicinal chemists in drug discovery. The information derived from the model was rationalized as a pharmacophore for competitive Pgp inhibition.
authors.affiliation: Laboratory of Chemometrics, Department of Chemistry, University of Perugia, Via Elce di Sotto 10, I-06123 Perugia, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Broccatelli
authors.forename: Emanuele
authors.initials: E
authors.lastname: Carosati
authors.forename: Annalisa
authors.initials: A
authors.lastname: Neri
authors.forename: Maria
authors.initials: M
authors.lastname: Frosini
authors.forename: Laura
authors.initials: L
authors.lastname: Goracci
authors.forename: Tudor I
authors.initials: TI
authors.lastname: Oprea
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cruciani
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000818:Animals; D000068180:Aripiprazole; D002090:Butyrophenones / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002090:Butyrophenones; D008024:Ligands; D010879:Piperazines; D010880:Piperidines; D015363:Quinolones; D000068180:Aripiprazole; C058249:ebastine