A topological substructural approach applied to the computational prediction of rodent carcinogenicity.
The carcinogenic activity has been investigated by using a topological substructural molecular design approach (TOPS-MODE). A discriminant model was developed to predict the carcinogenic and noncarcinogenic activity on a data set of 189 compounds. The percentage of correct classification was 76.32%. The predictive power of the model was validated by three test: an external test set (compounds not used in the develop of the model, with a 72.97% of good classification), a leave-group-out cross-validation procedure (4-fold full cross-validation, removing 20% of compounds in each cycle, with a good prediction of 76.31%) and two external prediction sets (the first and second exercises of the National Toxicology Program). This methodology evidenced that the hydrophobicity increase the carcinogenic activity and the dipole moment of the molecule decrease it; suggesting the capacity of the TOPS-MODE descriptors to estimate this property for new drug candidates. Finally, the positive and negative fragment contributions to the carcinogenic activity were identified (structural alerts) and their potentialities in the lead generation process and in the design of 'safer' chemicals were evaluated.
Helguera
Aliuska Morales
AM
Department of Chemistry, Faculty of Chemistry and Pharmacy, Central University of Las Villas, Santa Clara, 54830 Villa Clara, Cuba.
Cabrera Pérez
Miguel Angel
MA
González
Maykel Pérez
MP
Ruiz
Reinaldo Molina
RM
González Díaz
Humberto
H
D000818:Animals; D015197:Carcinogenicity Tests / Q000706:statistics & numerical data*; D002273:Carcinogens / Q000737:chemistry*; D003198:Computer Simulation; D016208:Databases, Factual / Q000706:statistics & numerical data; D008962:Models, Theoretical; D008968:Molecular Conformation; D011237:Predictive Value of Tests; D021281:Quantitative Structure-Activity Relationship; D012377:Rodentia
D002273:Carcinogens