Abstract

In this contribution, we attempted to design novel inhibitors of the serine/threonine-protein kinase Chk1. After studying the interaction of Chk1 ATP binding site with known inhibitor C39, we created seven modified C39-based molecules in order to achieve higher binding potentials. Of those, modified molecules 2, 4, 6 and 7 (MD2, MD4, MD6 and MD7) were selected to be assembled in three new molecules, originating MD8, MD9 and MD10. When compared to C39, MD8 and MD9 showed significant improvements in the binding energy while MD10 had a smaller gain. MD9 achieved the best improvement (21%) and MD8 the second best (19%) while MD10 only reached a 6% improvement.

Keywords: Checkpoint kinase 1, Chk1 inhibition, enzyme-inhibitor interactions, molecular design, semi-empirical calculations, p53-deficient tumor.

Graphical Abstract