A drug target is a biological molecule, usually a protein, whose activity a drug changes to produce a therapeutic effect. The target is the hypothesis; the drug molecule is the test of it.
Why a good molecule cannot rescue a bad target
A molecule can bind its intended protein tightly, avoid off-target effects, and reach the right tissue, and the program can still fail — because the protein it hits does not actually drive the disease. Optimization makes a molecule better at hitting the same protein; it does not change which protein that is. The failure lives in the hypothesis, not in the chemistry.
What "dominates downstream" means concretely
Every later stage — screening compound libraries, generating new molecules, balancing properties, predicting safety — is evaluated against the assumption that modulating this protein will change the disease. If the assumption is wrong, that work is not merely wasted effort on a hard problem; it is well-executed work aimed at the wrong place.