A Novel Approach for Predicting P-Glycoprotein (ABCB1) Inhibition Using Molecular Interaction Fields

Fabio Broccatelli, Emanuele Carosati, Annalisa Neri, Maria Frosini, Laura Goracci, Tudor I. Oprea, Gabriele Cruciani
2011 Journal of Medicinal Chemistry  
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
more » ... ing various MIF-based technologies, considering pharmacophoric features and those physico-chemical 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 'inhouse'. All 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. . Supporting Information IUPAC names and SMILES codes for the collected data; options for the calculations of Volsurf+ and Flap; details (Q 2 and R 2 ) of the PLS models; details of statistics (True Positives, True Negatives, False Positives, False Negatives) for the Training set, the Internal Validation set, and the External Validation set; analysis of chemical space of compounds from the Training set and the Validation sets; experimental data demonstrating the purity of the active compounds. This material is available free of charge via the Internet at
doi:10.1021/jm101421d pmid:21341745 pmcid:PMC3069647 fatcat:rxnqyl5fqvf2dailtxhptgbmvy