N⁺-C-H…O Hydrogen Bonds in Protein-Ligand Complexes and their Application to Drug Design

Abstract

In the context of drug design, C-H…O hydrogen bonds have received little attention so far, mostly because they are considered weak relative to other noncovalent interactions. Herein, we demonstrate the significance of hydrogen bonds between C-H groups adjacent to an ammonium cation and an oxygen atom (N⁺-C-H…O hydrogen bonds) in protein-ligand complexes. Quantum chemical calculations revealed the strength and geometrical requirements of these N⁺-C-H…O hydrogen bonds, and a subsequent survey of the Protein Data Bank based on the quantum chemical calculation results suggested that numerous protein-ligand complexes contain such N⁺-C-H…O hydrogen bonds. An ensuing experimental investigation into enzyme inhibitor complexes demonstrated that N⁺-C-H…O hydrogen bonds affect the activity of ligands against their target proteins. In addition, we identified histone demethylase inhibitors designed based on the formation of N⁺-C-H…O hydrogen bonds between them and their target protein. These results should provide the basis for the use of N⁺-C-H…O hydrogen bonds in drug discovery.