C-H•••O hydrogen bonds in the nuclear receptor RARγ -: a potential tool for drug selectivity

Hydrogen bonds between polarized atoms play a crucial role in protein interactions and are often used in drug design, which usually neglects the potential of C-H...O hydrogen bonds. The 1.4 Angstrom resolution crystal structure of the ligand binding domain of the retinoic acid receptor RAR(gamma) complexed with the retinoid SR11254 reveals several types of C-H...O hydrogen bonds. A striking example is the hydroxyl group of the ligand that acts as an H bond donor and acceptor, leading to a synergy between classical and C-H...O hydrogen bonds. This interaction introduces both specificity and affinity within the hydrophobic ligand pocket. The similarity of intraprotein and protein-ligand C-H...O interactions suggests that such bonds should be considered in rational drug design approaches.