Protein kinases are critical drug targets for treating a large variety of human diseases. Type-I and type-II kinase inhibitors frequently exhibit off-target toxicity or lead to mutation acquired resistance. Two highly specific allosteric type-III MEK-targeted drugs, Trametinib and Cobimetinib, offer a new approach. Thus, understanding the binding mechanism of existing type-III kinase inhibitors will provide insights for designing new type-III kinase inhibitors. In this work we have systematically studied the binding mode of MEK-targeted type-III inhibitors using structural systems pharmacology and molecular dynamics simulation. Our studies provide detailed sequence, structure, interaction-fingerprint, pharmacophore and binding-site information on the binding characteristics of MEK type-III kinase inhibitors. We propose that the helix-folding activation loop is a hallmark allosteric binding site for type-III inhibitors. Subsequently we screened and predicted allosteric binding sites across the human kinome, suggesting other kinases as potential targets suitable for type-III inhibitors. Our findings will provide new insights into the design of potent and selective kinases inhibitors.