Halogenation of organic compounds has been widely used in processes of hit-to-lead or lead-to-drug conversions and many drugs and drug candidates in clinical development contain halogen. 

The significance of halogen bonding, noncovalent intermolecular interaction occurred between Lewis bases (O, N and S) and Lewis acids (Cl, Br, and I), in protein-ligand interactions has been recognized recently.  

In an effort to understand the thermodynamic and structural characterization of halogen bonding in protein-ligand interactions, isothermal titration calorimetry combined with X-ray protein crystallography studies were carried out on the binding of the catalytic domain of cyclic nucleotide phosphodiesterase type 5 (PDE5) with different organohalogen inhibitors, which share an identical structure scaffold but have different substituents at 5-position of pyrimidinone ring.  

PDE5 is a prime drug target for treating diseases such as male erectile dysfunction and pulmonary arterial hypertension. ITC measurements show that the formation of halogen bonding between the chlorinated, brominated, or iodinated pyrimidin-4(3H)-one and protein are predominantly enthalpic-driven and the relevant binding free energies are -1.6, -3.1 and -5.59 kJ/mol, respectively.  

The solution thermodynamic properties of halogen bonding interactions in protein-ligand recognition are thus experimentally determined for the first time. Together with the geometry of halogen bonding provided by crystal structures of PDE5 in complex with inhibitors, the first structure-energy relationship of halogen bonding in protein-ligand interactions is obtained. 

In particular, the freshly determined crystal structure unexpectedly revealed that the strongest halogen bonding, -5.59 kJ/mol, is formed between the iodine of inhibitor and a buried water molecule but not the designed residue Y612.  

The discovery and characterization of such halogen bonding provide a representative case and shed light on the significance of halogen bonding to structural water for rational drug design. In addition, the unique chemical property of fluorine leads to the thermodynamic properties of the fluorinated inhibitor binding to PDE5 quite differently from those of chlorinated, brominated, and iodinated ones. A particular thermodynamic behavior of fluorinated ligand binding to protein is thus discussed on the basis of the complex structures and thermodynamic parameters. 

This study was accomplished by the research groups of Yechun Xu and Jingshan Shen in Shanghai Institute of Materia Medica,CAS. The results were published on the Journal of Medicinal Chemistry (2014, 57, 3588−3593). REN Jing and HE Yang are the co-first authors.  

Full text: http://pubs.acs.org/doi/abs/10.1021/jm5002315 

Figure 1 The binding of iodinated pyrimidin-4(3H)-one to PDE5. (A) The interactions between the residues and inhibitor revealed by the X-ray crystal structure (pdb code: 4OEW). (B) The thermodynamic properties of the inhibitor binding to the catalytic domain of PDE5. (Image by SIMM)