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 direction. Thus, understanding the binding mechanism of existing type-III kinase inhibitors will provide insights into improving the efficiency of designing and discovering such drugs. 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. Moreover, we have screened for similar target binding sites across the human kinome suggesting other potential kinase targets for type-III inhibitors.