Study of novel pyrazolo[3,4-d]pyrimidine derivatives as selective TgCDPK1 inhibitors: molecular docking, structure-based 3D-QSAR and molecular dynamics simulation

Abstract

Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) is a promising drug target to treat toxoplasmosis, and the selective TgCDPK1 inhibition over human kinases is significant for the development of potent antiparasitic TgCDPK1 inhibitors. In the present study, a total set of 46 pyrazolopyrimidine-based compounds possessing TgCDPK1 and Src inhibitory activity were studied by using a molecular modeling approach combining molecular docking, three dimensional quantitative structure–activity relationship (3D-QSAR) and molecular dynamics (MD) simulations. The best comparative molecular field analysis (CoMFA) models were established with satisfactory robustness and predictability, with R² = 0.968, q² = 0.666 and R_pred² = 0.745 for TgCDPK1 and R² = 0.970, q² = 0.581 and R_pred² = 0.635 for Src, respectively. Other tests on additional validations further confirmed the satisfactory predictive power of the models. The key residues impacting the interactions and the probable binding modes between inhibitor and enzymes (TgCDPK1 and Src) were identified by docking and further verified by MD simulations. Computational results demonstrated that bulky or electronegative substituents on R₂, and certain bulky groups attached to the terminal of R₁ may increase the potency of TgCDPK1 and TgCDPK1/Src selectivity. Finally, six new compounds showing high TgCDPK1 potency and TgCDPK1/Src selectivity were designed. We hope this study can be helpful for further development of novel potent TgCDPK1 selective inhibitors.