A topological substructural approach for the prediction of P-glycoprotein substrates.
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.
Cabrera
Miguel Angel
MA
Department of Drug Design, Centre of Chemical Bioactive, Central University of Las Villas, Santa Clara, Villa Clara, Cuba. macabrera@cbq.uclv.edu.cu
González
Isabel
I
Fernández
Carlos
C
Navarro
Carmen
C
Bermejo
Marival
M
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
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D024841:Fluoroquinolones; D004364:Pharmaceutical Preparations