Lead optimization, pharmacophore development and scaffold design of protein kinase CK2 inhibitors as potential COVID-19 therapeutics

Abstract

Therapeutic agents being designed against COVID-19 have targeted either the virus directly or the host cellular machinery. A particularly attractive host target is the ubiquitous and constitutively active serine-threonine kinase, Protein kinase CK2 (CK2). CK2 enhances viral protein synthesis by inhibiting the sequestration of host translational machinery as stress granules and assists in viral egression via association with the N-protein at filopodial protrusions of the infected cell. CK2 inhibitors such as Silmitasertib have been proposed as possible therapeutic candidates in COVID-19 infections. The present study aims to optimize Silmitasertib, develop pharmacophore models and design unique scaffolds to modulate CK2. The lead optimization phase involved the generation of compounds structurally similar to Silmitasertib via bioisostere replacement followed by a multi-stage docking approach to identify drug-like candidates. Molecular dynamics (MD) simulations were performed for two promising candidates (ZINC-43206125 and PC-57664175) to estimate their binding stability and interaction. Top scoring candidates from the lead optimization phase were utilized to build ligand-based pharmacophore models. These models were then merged with structure-based pharmacophores (e-pharmacophores) to build a hybrid hypothesis. This hybrid hypothesis was validated against a decoy set and used to screen a diverse kinase inhibitors library to identify favored chemical features in the retrieved actives. These chemical features include; an anion, an aromatic ring and an H-bond acceptor. Based on the knowledge of these features; de-novo scaffold design was carried out which identified phenindiones, carboxylated steroids, macrocycles and peptides as novel scaffolds with the potential to modulate CK2.

Communicated by Ramaswamy H. Sarma

KEYWORDS:

• Casein kinase
• CK2
• COVID-19
• kinase inhibitors
• lead optimization
• novel scaffolds
• pharmacophore development
• scaffold design
• silmitasertib

Acknowledgement

Siddharth Yadav is thankful for the financial assistance provided by Council of Scientific and Industrial Research (CSIR) and University Grants Commission (UGC), Government of India, under the Junior Research Fellowship scheme (NTA Ref No:201610275715). Shahzaib Ahamad is thankful for Research Associate, supported by the Indian Council of Medical Research, India, for financial assistance (2019-6039 File No: ISRM/11(83)/2019). Dinesh Gupta is endowed with funding by the Department of Biotechnology, Ministry of Science and Technology, Government of India (BT/PR40151/BTIS/137/5/2021), India.

Disclosure statement

The authors declare that they have no competing interests.

Author contributions

Siddharth Yadav contributed to the study design, data collection, molecular docking, pharmacophore development, analysis and interpretation of results and manuscript drafting. Shahzaib Ahamad contributed to MD simulations investigations and their write-up in the manuscript. Dinesh Gupta contributed to the MD data analysis, write-up and corrections in the manuscript. Puniti Mathur conceived and designed the analysis and corrected the manuscript. All authors have reviewed the results and approved the final version of the manuscript.