scaffold

A scaffold is the unchanging skeleton at the heart of a family of related molecules, the part everyone keeps the same while swapping decorations around its edges. Think of it as the chassis of a car onto which different wheels, seats, and trim can be bolted.

More precisely, it is the core molecular framework shared by a series of related drug compounds. Chemists attach different chemical groups, called substituents or R-groups, at various positions on the scaffold to tune potency, selectivity, and other properties.

Because the scaffold largely sets a molecule's overall shape and how it presents groups to the target, switching to a fundamentally different scaffold while keeping the same key interactions is a powerful design move known as scaffold hopping, often used to escape patents or fix unwanted properties.