Design of 2-amino-6-methyl-pyrimidine benzoic acids as ATP competitive casein kinase-2 (CK2) inhibitors using structure- and fragment-based design, docking and molecular dynamic simulation studies

ABSTRACT

Overexpression of casein kinase-2 (CK2) has been implicated in several carcinomas, mainly lung, prostate and acute myeloid leukaemia. The smaller nucleotide pocket compared to related kinases provides a great opportunity to discover newer ATP-competitive CK2 inhibitors. In this study, we have employed an integrated structure- and fragment-based design strategy to design 2-amino-6-methyl-pyrimidine benzoic acids as ATP-competitive CK2 inhibitors. A statistically significant four features-based E-pharmacophore (ARRR) model was used to screen 780,092 molecules. Further, the retrieved hits were considered for molecular docking study to identify essential binding interactions. At the same time, fragment-based virtual screening was performed using a dataset of 1,542,397 fragments. The identified hits and fragments were used as structure templates to rationalize the design of 2-amino-6-methyl-pyrimidine benzoic acids as newer CK2 inhibitors. Finally, the binding interactions of the designed hits were identified using an induced fit docking (IFD) study, and their stability was estimated by a molecular dynamics (MD) simulation study of 100 ns.

KEYWORDS:

• Casein kinase-2 inhibitors
• 2-amino-6-methyl-pyrimidine benzoic acids
• fragment-based design
• molecular docking
• MD simulations

Acknowledgements

This article is supported by the Post-doctoral fellowship by Nirma University, Ahmedabad. This project is also supported by a minor research project (MRP) grant from Nirma University, Ahmedabad, Gujarat, India (NU/DRI/MinResPrj/lP/202l-22) to Vivek K. Vyas.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed at: https://doi.org/10.1080/1062936X.2023.2196091

Additional information

Funding

This work was supported by the Institute of Pharmacy, Nirma University [NU/DRI/MinResPrj/lP/202l-22].