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

Gergely      Toth; Simeon   G.   Bowers; Anh   P.   Truong; Gary      Probst

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.

Keywords: Weakly polar interaction, unconventional hydrogen bond, blue-shifting hydrogen bond, N-H...π interaction, O-H...π interaction, π...π interaction, C-H...O interaction, C-H...F-C interaction, N-H...F-C interaction, O-H...F-C interaction