title: A topological substructural approach for the prediction of P-glycoprotein substrates.
abstract: A topological substructural molecular design approach (TOPS-MODE) has been used to predict whether a given compound is a P-glycoprotein (P-gp) substrate or not. A linear discriminant model was developed to classify a data set of 163 compounds as substrates or nonsubstrates (91 substrates and 72 nonsubstrates). The final model fit the data with sensitivity of 82.42% and specificity of 79.17%, for a final accuracy of 80.98%. The model was validated through the use of an external validation set (40 compounds, 22 substrates and 18 nonsubstrates) with a 77.50% of prediction accuracy; fivefold full cross-validation (removing 40 compounds in each cycle, 80.50% of good prediction) and the prediction of an external test set of marketed drugs (35 compounds, 71.43% of good prediction). This methodology evidenced that the standard bond distance, the polarizability and the Gasteiger-Marsilli atomic charge affect the interaction with the P-gp; suggesting the capacity of the TOPS-MODE descriptors to estimate the P-gp substrates for new drug candidates. The potentiality of the TOPS-MODE approach was assessed with a family of compounds not covered by the original training set (6-fluoroquinolones), and the final prediction had a 77.7% of accuracy. Finally, the positive and negative substructural contributions to the classification of 6-fluoroquinolones, as P-gp substrates, were identified; evidencing the possibilities of the present approach in the lead generation and optimization processes.
authors.affiliation: Department of Drug Design, Centre of Chemical Bioactive, Central University of Las Villas, Santa Clara, Villa Clara, Cuba. macabrera@cbq.uclv.edu.cu
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Cabrera
authors.forename: Isabel
authors.initials: I
authors.lastname: González
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández
authors.forename: Carmen
authors.initials: C
authors.lastname: Navarro
authors.forename: Marival
authors.initials: M
authors.lastname: Bermejo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D003198:Computer Simulation; D024841:Fluoroquinolones / Q000145:classification / Q000378:metabolism; D016014:Linear Models; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000145:classification / Q000378:metabolism*; D011237:Predictive Value of Tests; D021281:Quantitative Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D024841:Fluoroquinolones; D004364:Pharmaceutical Preparations