Small change for a big improvement – halogen bonds and drug discovery

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Halogen chemistry has been exploited by medicinal chemists for nearly 70 years. To date, halogens were regarded useful for optimisation of so-called ADMET properties (the acronym stands for absorption, distribution, metabolism, excretion, toxicity) – they improve oral absorption and facilitate crossing biological barriers by prospective drugs, they are useful for filling small hydrophobic cavities present in many protein targets, and they prolong lifetime of the drug. In other words, making compounds of interest more drug-like. However, direct interactions mediated by halogen atoms have been much ignored in pre-clinical drug development.

Halogens (except fluorine) have unique properties which allow them to stabilise direct interaction between prospective drugs and their protein targets. These properties are of quantum-chemical origin; namely, the anisotropy of charge distribution around the halogen atom, when it is bound to an electron-withdrawing substrate. Unexpectedly, despite of being negatively charged, halogens have regions which remain positively charged (Figure 1, left panel). These regions, called sigma-holes, are responsible for directional and stabilising character of halogen bonding with other electronegative atoms, such as oxygen or nitrogen.

Overlooking sigma-hole lead to errors in predictions of structure and energetics of drug protein complexes and thus to failure in drug development.

Recently, scientists working in quantum chemistry and structure-based drug design have developed the tool for usage of halogen bonds for computational medicinal chemistry and drug discovery applications. By approximating the positively charged sigma-hole with massless, charged pseudo-atom (denoted as explicit sigma-hole or ESH), they incorporated quantum-chemical effect into faster (and much less accurate) computational methods, applicable to structure-based drug design. Tests performed on nearly a hundred complexes between medicinally relevant proteins and halogenated molecules showed significant improvement in description of such complexes upon introduction of ESH (Figure 1, right panel). The new method is already used for design of novel compounds for treatment of chemotherapy-resistant cancers, infectious diseases, and Alzheimer disease.

The study has been led by Dr. Agnieszka Bronowska from Heidelberg Institute for Theoretical Studies (HITS) in Heidelberg and conducted in cooperation with scientists from Czech Academy of Sciences, Prague. It has been described in Chemical Communications.