methyl scan
If you wanted to find the ticklish spot on a molecule, you could poke it gently in many places, one at a time, and watch where it reacts. A methyl scan does just that: a chemist makes a set of analogs that each add a single small methyl group at a different position, then tests them to see where the methyl helps, hurts, or does nothing.
Concretely, a methyl scan systematically installs a CH3 group, one position at a time, around a lead molecule. The methyl is a minimal, chemically simple probe: where it boosts potency it usually marks a small hydrophobic gap in the pocket or a conformational preference being locked in; where it kills potency it signals a steric clash; and where it does nothing it suggests open space or solvent exposure. Each result is a matched molecular pair against the unsubstituted parent.
The methyl scan is prized because methyl groups add little molecular weight and lipophilicity, so the readout is relatively clean. Its limit is breadth: a single small probe cannot reveal what a larger group, a polar group, or a heteroatom replacement would do, so a methyl scan is a first reconnaissance, not the whole campaign.
Methylating each of six positions on an aromatic ring in turn shows that one ortho methyl triples potency while the rest are neutral or harmful, focusing the next designs on that single hot position.
A small, uniform probe maps which positions on the molecule matter most.
Occasionally a single methyl in a methyl scan gives a huge, unexpected jump in potency — the magic methyl effect — which is the most exciting and least predictable outcome of the exercise.