Docking of protein kinase B inhibitors: implications in the structure-based optimization of a novel scaffold

Protein kinase B (PKB/AKT) is an attractive therapeutic target in anticancer drug development. We have recently identified by docking-based virtual screening a low micromolar AKT-2 inhibitor. Additionally, the virtual screening hit represents a novel AKT-2 inhibitor scaffold. In this work, we discuss a structure-based design strategy toward the optimization of this hit. Following this strategy and using a herein validated docking protocol, we conducted the design of novel compounds with expected improved activity over the parent compound. The newly designed molecules have high predicted affinity for AKT-2; are synthetically accessible and are contained within the kinase-relevant property space.