Physics

Bond energy

Solvation

Bond length

Chalcogen

Chemical bond

Organic chemistry

Three-center two-electron bond

Hydrogen

Crystallography

Single bond

Hydrogen bond

Bond order

Low-barrier hydrogen bond

Computational chemistry

Halogen bond

Chemistry

Condensed matter physics

Acceptor

Molecule

Alkyl

Sextuple bond

Photochemistry

Journal of Medicinal Chemistry

Hydrogen-bond donors are seen to cause more problems for drug designers than hydrogen-bond acceptors. Most of the polarity in drug-like compounds comes from hydrogen-bond acceptors since they typically exceed the hydrogen-bond donors in number and are more heavily solvated on an individual basis. The implications of this polarity imbalance for optimization of permeability and aqueous solubility are discussed. A factor that should be considered in optimization of ligand recognition by targets is that the presence of a hydrogen-bond donor generally implies that a hydrogen-bond acceptor is also present (but not vice versa). Frustrated solvation and secondary electrostatic interactions result from aligned hydrogen-bond donors and acceptors, and the design opportunities presented by these phenomena are discussed. Hydrogen-bond donors based on oxygen, nitrogen and carbon are compared as target recognition elements, and halogen- and chalcogen-bond donors are discussed as hydrogen-bond donor equivalents.

Hydrogen-Bond Donors in Drug Design