Jump to main content
Jump to site search
PLANNED MAINTENANCE Close the message box

Scheduled maintenance upgrade on Thursday 4th of May 2017 from 8.00am to 9.00am (BST).

During this time our websites will be offline temporarily. If you have any questions please use the feedback button on this page. We apologise for any inconvenience this might cause and thank you for your patience.


Issue 103, 2016, Issue in Progress
Previous Article Next Article

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

Author affiliations

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 Rpred2 = 0.745 for TgCDPK1 and R2 = 0.970, q2 = 0.581 and Rpred2 = 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.

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

Back to tab navigation
Please wait while Download options loads

Supplementary files

Publication details

The article was received on 11 Aug 2016, accepted on 11 Oct 2016 and first published on 11 Oct 2016


Article type: Paper
DOI: 10.1039/C6RA20277B
Citation: RSC Adv., 2016,6, 100772-100782
  •   Request permissions

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

    S. Ma, S. Zhou, W. Lin, R. Zhang, W. Wu and K. Zheng, RSC Adv., 2016, 6, 100772
    DOI: 10.1039/C6RA20277B

Search articles by author