Abstract
In the current study, quantitative three-dimensional structure-activity -relationship (3D-QSAR) method was performed to design a model for new chemical entities by utilizing pyrazolopyrimidines. Their inhibiting activity on receptor IL-2 Itk correlates descriptors based on topology and hydrophobicity. The best model developed by ligand-based (atom-based) approach has correlation-coefficient of r(2): 0.987 and cross-validated squared correlation-coefficient of q(2): 0.541 with an external prediction capability of r(2): 0.944. Whereas the best selected model developed by structured-based (receptor-based) approach has correlation-coefficient of r(2): 0.987, cross-validated squared correlation-coefficient of q(2): 0.637 with an external predictive ability of r(2): 0.941. The statistical parameters prove that structure-based gave a better model to design new chemical scaffolds. The results achieved indicated that hydrophobicity at R-1 location play a vital role in the inhibitory activity and introduction of appropriately bulky and strongly hydrophobic-groups at position 3 of the terminal phenyl-group which is highly significant to enhance the activity. Six new pyrazolopyrimidine derivatives were designed. Docking simulation study was carried out and their inhibitory activity was predicted by the best structure based model with predictive activity of ranging from 8.43 to 8.85 log unit. The interacting residues PHE435, ASP500, LYS391, GLU436, MET438, CYS442, ILE369, VAL377 of PDB 4HCT were studied with respect to type of bonding with the new compounds. This study was aimed to search out more potent inhibitors of IL-2 Itk. (C) 2017 Elsevier Inc. All rights reserved.