Protein kinases are involved in most aspects of cell life due to their role in signal transduction. Their dysregulation can cause severe diseases such as cancer, inflammation, and neurodegeneration, which makes them a frequent target of drug discovery campaigns. In 2015, 30% of FDA-approved small molecules targeted kinases. The roughly 500 kinases in the human genome share a highly conserved binding site, which challenges selective drug design for a single kinase or a well-defined set of kinases (polypharmacology) avoiding binding to undesired off-targets. Protein kinases bind adenosine triphosphate (ATP) to catalyze the transfer of its phosphate group to serine, threonine, or tyrosine residues of themselves or other proteins. ATP and most other ligands bind to the front cleft of the kinase pocket that lays between the two kinase domains, the C-and N-terminal lobes. These domains are connected via a hinge region, which is forming important hydrogen bonds to ATP as well as most studied ligands.