What's the charge on iodine

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01/27/13 Molecular cage binds iodine or bromine

Halogens in drug development

Fig. 1: Left side: Charge distribution around the bromobenzene molecule. Regions with negative electrostatic potential are marked in blue, positively charged regions in gray. The gray disk in the foreground marks the sigma hole. Right side: Overlay of the predicted binding sites of the K17 inhibitor of casein kinase 2 (PDB code 2OXY) with explicit sigma holes (red) and without (blue) and comparison with the crystal structure (gray).
Source: Agnieszka Bronowska, Heidelberg Institute for Theoretical Studies gGmbH (HITS)

Halogen chemistry has been used by medicinal chemists for nearly 70 years. So far, halogens have been used to optimize the ADMET properties. The English abbreviation stands for absorption (absorption into the bloodstream), distribution (distribution in the organism), metabolism (metabolism), excretion (excretion) and toxicity (toxicity). Halogens improve oral uptake and make it easier for potential drugs to cross biological barriers. They help fill small hydrophobic cavities in many target proteins and extend the duration of the drug's action. In short, they turn promising chemical compounds into potential drugs. However, interactions involving halogen atoms have been largely neglected in pre-clinical drug development.

Researchers from the fields of quantum chemistry and structure-based drug development in Heidelberg and Prague have now developed a new process to use halogen compounds in computer-aided medicinal chemistry and for applications in drug research. The study led by Dr. Agnieszka Bronowska from the Heidelberg Institute for Theoretical Studies (HITS) involved researchers from the Academy of Sciences of the Czech Republic.

Most halogens (except fluorine) have unique properties that enable them to stabilize interactions between potential drugs and their target proteins. These properties are of quantum chemical origin: They are based on anisotropy, i.e. the directional dependence of the charge distribution around the halogen atom when it binds to a substrate that withdraws electrons from the atom. Surprisingly, despite a negative charge, halogens have regions that still have a positive charge (Figure 1, left-hand side). These regions are known as sigma holes and are responsible for the directional and stabilizing character of halogen bonds with other electronegative atoms such as oxygen or nitrogen.

Failure to factor in sigma holes in predicting the structure and energetics of drug-protein complexes can lead to errors that can lead to drug development failures.

In the new method, the positively charged sigma holes are approximated with a massless, charged pseudo-atom. This is known as the "explicit sigma hole". This enabled Agnieszka Bronowska and her colleagues to integrate a quantum chemical effect into faster (and much less precise) computer-aided analysis methods in structure-based drug development. “We tested almost one hundred complexes made from medically relevant proteins and halogenated molecules,” says the researcher. "The results showed a significant improvement in the description of such complexes after the introduction of the explicit sigma hole."

The new process is already being used by research groups in the Czech Republic, Great Britain and the USA to develop novel compounds for the treatment of chemotherapy-resistant cancers, infectious diseases and Alzheimer's.


Plugging the explicit sigma holes in molecular docking
M. Kolár, et. al., Chem. Commun.2012. DOI: 10.1039 / C2CC37584B

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Molecular cage binds iodine or bromine
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