High throughput screening, docking, and molecular dynamics studies to identify potential inhibitors of human calcium/calmodulin-dependent protein kinase IV

Abstract

Calcium/calmodulin-dependent protein kinase IV (CAMKIV) is associated with many diseases including cancer and neurodegenerative disorders and thus being considered as a potential drug target. Here, we have employed the knowledge of three-dimensional structure of CAMKIV to identify new inhibitors for possible therapeutic intervention. We have employed virtual high throughput screening of 12,500 natural compounds of Zinc database to screen the best possible inhibitors of CAMKIV. Subsequently, 40 compounds which showed significant docking scores (−11.6 to −10.0 kcal/mol) were selected and further filtered through Lipinski rule and drug likeness parameter to get best inhibitors of CAMKIV. Docking results are indicating that ligands are binding to the hydrophobic cavity of the kinase domain of CAMKIV and forming a significant number of non-covalent interactions. Four compounds, ZINC02098378, ZINC12866674, ZINC04293413, and ZINC13403020, showing excellent binding affinity and drug likeness were subjected to molecular dynamics simulation to evaluate their mechanism of interaction and stability of protein-ligand complex. Our observations clearly suggesting that these selected ligands may be further employed for therapeutic intervention to address CAMKIV associated diseases.

Communicated by Ramaswamy H. Sarma

Keywords:

• Calcium/calmodulin-dependent protein kinase IV
• molecular docking
• virtual screening
• MD simulations
• kinase inhibitors
• transcriptional regulation

Acknowledgments

AB is thankful to the Jamia Millia Islamia, New Delhi, India, for the award of non-NET fellowship. FIK and KL thank to the Centre for High Performance Computing (CHPC), South Africa.

Disclosure statement

Authors declare no conflict of interest regarding any financial and personal relationships with other people or organizations that could inappropriately influence (bias) this work.

Additional information

Funding

MIH thank to Indian Council of Medical Research for the financial support (Project No. BIC/12(01)/2015).