Hydrogen bond donors in drug design

In medicinal chemistry, hydrogen bond donors are seen to cause more problems than hydrogen bond acceptors and this study examines hydrogen bond donor-acceptor asymmetries in the context of drug design. Hydrogen bond acidity is reviewed and it is shown how polarity can be estimated for individual hydrogen bond donors and acceptors from alkane/water partition coefficient measurements. Hydrogen bond donors are generally less polar than hydrogen bond acceptors and desolvation penalty is therefore an implausible explanation for deleterious effects of hydrogen bond donors. Generally, the number of hydrogen bond acceptors in organic compounds exceeds the number of hydrogen bond donors and the apparently greater restrictiveness of the Rule of 5 for hydrogen bond donors may simply be a reflection of this imbalance. The weaker hydration of hydrogen bond donors implies that attempts to address polarity surfeit in optimization of permeability should be focused on hydrogen bond acceptors. Elimination of redundant hydrogen bond donors can potentially reduce active efflux and destabilize the solid state without resulting in unacceptable increases in lipophilicity. The key hydrogen bond donor-acceptor asymmetry in the context of target recognition is that the presence of a hydrogen bond donor usually implies that a hydrogen bond acceptor is also present. Target-ligand hydrogen bonds form in aqueous media and design opportunities presented by frustrated hydration and secondary interactions are discussed. Hydrogen bond donors based on oxygen, nitrogen and carbon are compared as target recognition elements and potential benefits of halogen and chalcogen bond donors as replacements for hydrogen bond donors are discussed.