N+-C-H···O hydrogen bonds in protein-ligand complexes and their application to drug design

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. © 2020 Society of Synthetic Organic Chemistry. All rights reserved.