Computational Molecular Modeling of Pin1 Inhibition Activity of Quinazoline, Benzophenone, and Pyrimidine Derivatives

Abstract

Pin1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) is directly involved in cancer cell-cycle regulation because it catalyses the cis-trans isomerization of prolyl amide bonds in proteins. In this sense, a modeling evaluation of the inhibition of Pin1 using quinazoline, benzophenone, and pyrimidine derivatives was performed by using multilinear, random forest, SMOreg, and IBK regression algorithms on a dataset of 51 molecules, which was divided randomly in 78% for the training and 22% for the test set. Topological descriptors were used as independent variables and the biological activity (pIC50) as a dependent variable. The most robust individual model contained 9 features, and its predictive capability was statistically validated by the correlation coefficient for adjusting, 10-fold cross validation, test set, and bootstrapping with values of 0.910, 0.819, 0.841, and 0.803, respectively. In order to improve the prediction of the pIC50 values, the aggregation of the individual models was performed through the construction of an ensemble, and the most robust one was constructed by two individual models (LR3 and RF1) by applying the IBK algorithm, and a substantial improvement in predictive performance is reflected in the values of R2ADJ = 0.982, Q2CV = 0.962, and Q2EXT = 0.918. Mean square errors <0.165 and good fitting between calculated and experimental pIC50 values suggest a robustness on the prediction of pIC50. Regarding the docking simulation, a binding affinity between the molecules and the active site for the Pin1 inhibition into the protein (3jyj) was estimated through the calculation of the binding free energy (BE), with values in the range of −5.55 to −8.00 kcal/mol, implying a stabilizing interaction molecule receptor. The ligand interaction diagrams between the drugs and amino acid in the binding site for the three most active compounds denoted a good wrapper of these organic compounds into the protein mainly by polar amino acids.