The ERK path is among the most significant signaling cascades involved with tumorigenesis. To date, eight noncovalent inhibitors of RAF and MEK kinases within the ERK path happen to be authorized by the Food and drug administration to treat cancers however, their efficacies are restricted because of various resistance mechanisms. There’s a sudden have to develop novel targeted covalent inhibitors. Ideas report an organized study from the covalent ligandabilities from the ERK path kinases (ARAF, BRAF, CRAF, KSR1, KSR2, MEK1, MEK2, ERK1, and ERK2) using constant pH molecular dynamics titration and pocket analysis. Our data says the hinge GK (gate keeper) 3 cysteine in RAF family kinases (ARAF, BRAF, CRAF, KSR1, and KSR2) and also the back loop cysteine in MEK1 and MEK2 are reactive and ligandable. Structure analysis shows that the kind II inhibitors belvarafenib and GW5074 can be utilized as scaffolds for designing pan-RAF or CRAF-selective covalent inhibitors fond of the GK 3 cysteine, as the type III inhibitor cobimetinib might be modified to label the rear loop cysteine in MEK1/2. The reactivities and ligandabilities from the remote cysteine in MEK1/2 and also the DFG-1 cysteine in MEK1/2 and ERK1/2 will also be discussed. Our work supplies a beginning point for medicinal chemists to create novel covalent inhibitors from the ERK path kinases. The computational protocol is general and could be put on the systematic look at covalent ligandabilities from the human cysteinome.