Rational design of kinase inhibitors remains a challenge partly because there is no clear delineation of the molecular features that direct the pharmacological impact towards clinically relevant targets. Standard factors governing ligand affinity, such as potential for intermolecular hydrophobic interactions or for intermolecular hydrogen bonding do not provide good markers to assess cross reactivity. Thus, a core question in the informatics of drug design is what type of molecular similarity among targets promotes promiscuity and what type of molecular difference governs specificity. This work answers the question for a sizable screened sample of the human pharmacokinome including targets with unreported structure.