Structure- and ligand-based structure-activity relationships for a series of inhibitors of aldolase.
Aldolase has emerged as a promising molecular target for the treatment of human African trypanosomiasis. Over the last years, due to the increasing number of patients infected with Trypanosoma brucei, there is an urgent need for new drugs to treat this neglected disease. In the present study, two-dimensional fragment-based quantitative-structure activity relationship (QSAR) models were generated for a series of inhibitors of aldolase. Through the application of leave-one-out and leave-many-out cross-validation procedures, significant correlation coefficients were obtained (r²=0.98 and q²=0.77) as an indication of the statistical internal and external consistency of the models. The best model was employed to predict pKi values for a series of test set compounds, and the predicted values were in good agreement with the experimental results, showing the power of the model for untested compounds. Moreover, structure-based molecular modeling studies were performed to investigate the binding mode of the inhibitors in the active site of the parasitic target enzyme. The structural and QSAR results provided useful molecular information for the design of new aldolase inhibitors within this structural class.
Laboratório de Quimica Medicinal e Computacional, Instituto de Física de São Carlos, Universidade de São Paulo, Av. Trabalhador São-Carlense 400, 13560-970, São Carlos- SP, Brazil.
Leonardo G
LG
Ferreira
Adriano D
AD
Andricopulo
D001185:Artificial Intelligence; D020134:Catalytic Domain; D019295:Computational Biology / Q000379:methods*; D030562:Databases, Protein; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005634:Fructose-Bisphosphate Aldolase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D021621:Imaging, Three-Dimensional; D007700:Kinetics; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000201:enzymology
D004791:Enzyme Inhibitors; D008024:Ligands; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; D005634:Fructose-Bisphosphate Aldolase