High-throughput Docking and Molecular Dynamics Simulations towards the Identification of Novel Peptidomimetic...

Inhibition protein-protein interactions (PPIs) using small molecules, that interfere with the formation of these complexes, modulates critical regulatory pathways and has therapeutic significance. DBF4-dependent kinase CDC7 is the S-phase checkpoint pathway target, which plays an important role for a proper response to DNA damage and replicative stress in multiple organisms. Overexpression of CDC7 and its protein regulator DBF4 is highly neurotoxic and promotes cancer and neurodegeneration. In the present study, virtual screening of inhibitor scaffolds mimicking DBF4 pharmacophoric properties was carried out and evaluation of their potential inhibitory activity toward CDC7 was performed using high-throughput docking and molecular dynamics simulations. The calculations identified five small molecules exhibiting a high affinity to the active site region of the CDC7 protein.