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.
Highlights
Pin1 has been used as a target for treating cancer since its discovery [1] because it plays a critical role in cell-cycle regulation, it catalyses the cis-trans isomerization of prolyl amide bonds in its substrate proteins, and deregulated proteins are common human cancer cells [2]
Compound 52 was considered as outlier based on the statistical parameters and adjusted on the training and test set; in addition, it is well-known in the literature that it failed to show cellular e ects due to the poor permeability of the phosphate group [27]. eir biological activity expressed as IC50 was collected from the literature by the Bailing Xu research group, where 17 possess quinazoline structures (Table S1 in the supplementary material) [11], 9 are benzophenone structure (Table S2 in the supplementary material) [12], and 26 of the molecules possess pyrimidine and naphthalemic nucleus (Table S3 in the supplementary material) [13]
A molecular modeling simulation for the Pin1 inhibition by an organic compound containing an aromatic ring in their structure was evaluated by using quantitative structure-activity relationship (QSAR) approach
Summary
Pin has been used as a target for treating cancer since its discovery [1] because it plays a critical role in cell-cycle regulation, it catalyses the cis-trans isomerization of prolyl amide bonds in its substrate proteins, and deregulated proteins are common human cancer cells [2]. With respect to the lastmentioned compounds, the Bailing Xu’s group had reported the synthesis of several compounds as potential Pin inhibitors. In their earlier e orts, in 2011, they synthesized 2,4disubstituted quinazoline derivatives (Scheme 1). E most potential inhibitor, compound 13, with the 50% inhibitory concentration (IC50) equal to 2.90 μM, has two chlorine atoms bonded in the position 3 of the aromatic ring on the substituent R4, a carboxylic acid linked to the benzene in the position R5, and an NO2 group in the quinazoline nucleus.
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