Binding free energy-guided design of Protein kinase CK2 inhibitors and structure-activity relationship analysis

Abstract

In drug design study, it is often observed that a very small structural modification such as introducing a methyl group or a chlorine atom to the known inhibitor causes large enhancement of the inhibitory activity. However, it is difficult to predict such an activity change from structural information even if the structure-based drug design method is utilized. Therefore, selection of such compounds guided by calculated binding energy from candidate compounds is one of the efficient ways. In this study, we employed the thermodynamic integration method for the prediction of binding free energy change between two compounds to explore more potent CK2 inhibitors by introducing a chlorine atom to the known inhibitor. CK2 is a kind of serine/threonine protein kinases and is a target protein for the treatment of cancer and nephritis. Since a part of compounds were predicted more potent than the base compound, we synthesized and evaluated their inhibitory activities, and their structure-activity relationship was analyzed.