hydrogen-bond donors

A hydrogen-bond donor is a part of a molecule that offers up a hydrogen atom to be shared with a neighbor, forming a hydrogen bond. In practice these are hydrogens attached to oxygen or nitrogen, such as the OH of an alcohol, the NH of an amine, or the NH in an amide bond. Think of each as a tiny outstretched hand looking to clasp a partner.

Counting donors is a quick, structure-based property. It matters because each donor anchors a shell of water that must be peeled off for the molecule to cross a fatty membrane, so a high donor count tends to lower permeability and oral absorption. Lipinski's rule of five flags more than five donors as a warning sign.

Donors are not merely a liability: the very same groups often make crucial hydrogen bonds to a drug's target, contributing potency and selectivity. The art is to keep the donors that earn their keep at the binding site and trim or mask the rest, for example by capping an NH or tucking it into an intramolecular hydrogen bond.