Design, identification, optimisation and validation of selective casein kinase (CK2) modulators

Abstract

Casein Kinase II (CK2) has been acknowledged as a key contributor to carcinogenesis and has been identified as a druggable target in oncology because its inhibition slows down cellular metabolism. GO289, has been identified as a promising molecule for the mitigation of phosphorylation of circadian proteins and proliferation of malignant cells through CK2 inhibition. This study aimed to probe the CK2 ligand binding pocket and identify high-affinity analogues to target CK2 in a similar way as the lead molecule GO289. In silico, structure-based drug design approaches adopted in this study were Virtual Screening and de novo design. The molecular cohort obtained through Virtual Screening was important because it proposed novel scaffolds capable of CK2 modulation. A fundamental hypothesis in structure-based drug design is that a superior CK2 modulator should have a high binding affinity to the target. De novo molecules obtained in this study were Lipinski Rule compliant and found to have higher binding affinities when compared to the lead molecule, making them suitable candidates for further optimisation and validation.