The Role and Significance of Unconventional Hydrogen Bonds in Small Molecule Recognition by Biological Receptors of Pharmaceutical Relevance

Abstract

The discovery and optimization of nonbonded interactions, such as van der Waals interactions, hydrogen bonds, salt bridges and the hydrophobic effect, between small molecule ligands and their receptors is one of the main challenges in rational drug discovery. As the theory of molecular interactions advances more evidence accumulates that nonbonded interactions, such as unconventional hydrogen bonds (X-H...Y interactions, where X can be either C, N or O atom and Y can be either an aromatic ring system O or F atom), contribute to ligand recognition by biological receptors. This review provides an overview of unconventional hydrogen bonds between ligands and their receptors of pharmaceutical relevance by dissecting their structure activity relationships and 3D structural elements. Gaining an understanding of the energetic and the structural properties of unconventional hydrogen bonds in ligand-receptor interactions leads us to the elucidation of their practical significance. Ultimately, this enables us to consciously apply these interactions in hit and lead optimization in rational structure based drug design.

Refined structures of mouse P‐glycoprotein

“…The presentation of charged residues by lipid flippases to the hydrophobic section of the bilayer is reminiscent of α‐helical proteins and amphipathic α‐helical peptides that exhibit reversible lipid binding in a membrane . Taken together, the composition of the 46 residues of the translocation pathway in Pgp provides structural evidence that a significant amount of drug–protein interaction is likely to be electrostatic, including a strong component of cation–π, CH–π, or π–π recognition . The aromatic residues in the mouse Pgp drug translocation pathway could provide strong affinity for substrates with lower geometric constraints compared to hydrogen bonding, and a consequentially lower entropic penalty of binding drug substrates.…”

Importance of CH/π hydrogen bonds in recognition of the core motif in proline‐recognition domains: An Ab initio fragment molecular orbital study

“…A CH/π hydrogen bond is a weak molecular interaction, such as CH/O,15 OH/π,16 and NH/π 17. Such hydrogen bonds have often been observed in biomolecules 18–20. The energy of one CH/π hydrogen bond is ∼1.5–2.5 kcal/mol for aliphatic or aromatic CH groups 21, 22.…”

Hydrogen Bonding of 1,2-Azaborines in the Binding Cavity of T4 Lysozyme Mutants: Structures and Thermodynamics

“…21,22 Hydrogen bonds are widely accepted as crucial in drug-receptor binding 23–26 and in maintaining favorable physical properties, and they are often installed in the course of a drug design campaign. 27–29 Whether the NH of the 1,2-azaborine can participate in hydrogen bonds, and how these compare quantitatively to more familiar ligand-protein hydrogen bonds, also remains unexplored.…”