rotatable bonds

Rotatable bonds count the single bonds in a molecule around which the two halves can freely swivel, like the hinges and joints that let a string of beads flop into many shapes. The more such bonds, the floppier and more flexible the molecule.

By convention they are non-ring single bonds between two non-terminal heavy atoms (so a methyl group's bond and double or triple bonds do not count). The number is a cheap, structure-derived gauge of flexibility, and it carries a cost: a very floppy molecule pays an entropy penalty when it freezes into a single shape to bind a target, and flexibility also tends to hurt oral absorption.

Veber's analysis found that keeping rotatable bonds to ten or fewer, alongside a modest polar surface area, predicts good oral bioavailability. A common design tactic is conformational restriction, locking a flexible chain into a ring so the molecule is preorganized into its binding shape, which can simultaneously boost potency and improve drug-like properties.