Jan. 18, 2013 ? Halogen fastening has been practical in clear engineering, materials research, and nanotechnology for some time. Scientists from a Heidelberg Institute for Theoretical Studies (HITS) and a Czech Academy of Science in Prague have now grown a new apparatus to use halogen holds for drug find applications.
Halogen chemistry has been exploited by medicinal chemists for scarcely 70 years. To date, halogens were regarded useful for optimization of supposed ADMET properties (the acronym stands for absorption, distribution, metabolism, excretion, toxicity) — they urge verbal fullness and promote channel biological barriers by impending drugs, they are useful for stuffing tiny violent cavities benefaction in many protein targets, and they lengthen lifetime of a drug. In short: They make compounds of seductiveness some-more drug-like. However, approach interactions mediated by halogen atoms have been most abandoned in pre-clinical drug development.
Recently, scientists from Heidelberg and Prague, operative in quantum chemistry and structure-based drug design, have grown a new apparatus for a use of halogen holds for computational medicinal chemistry and drug find applications. The study, led by Dr. Agnieszka Bronowska from a Heidelberg Institute for Theoretical Studies (HITS) and conducted in team-work with scientists from a Czech Academy of Sciences, has been published in Chemical Communication.
Most halogens — solely fluorine — have singular properties that concede them to stabilise approach communication between impending drugs and their protein targets. These properties are of quantum-chemical origin; namely, a anisotropy of assign placement around a halogen atom, when it is firm to an electron-withdrawing substrate. Unexpectedly, notwithstanding of being negatively charged, halogens have regions that sojourn definitely charged (image, left panel). These regions, called sigma-holes, are obliged for a directional and stabilizing impression of halogen fastening with other electronegative atoms, such as oxygen or nitrogen. Overlooking sigma-holes leads to errors in predictions of structure and energetics of drug-protein complexes and so to disaster in drug development.
By approximating a definitely charged sigma-hole with a massless, charged pseudo-atom (denoted as pithy sigma-hole or ESH), Agnieszka Bronowska and her colleagues incorporated a quantum-chemical outcome into faster (and most reduction accurate) computational methods germane to structure-based drug design. “We tested scarcely a hundred complexes between medicinally applicable proteins and halogenated molecules,†Bronowska says. “The formula showed poignant alleviation in a outline of such complexes on introduction of ESH.â€
The new process is already used by investigate groups in a Czech Republic, in a United Kingdom and in a U.S. for conceptualizing novel compounds to yield chemotherapy-resistant cancers, spreading diseases, and Alzheimer’s disease.
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The above story is reprinted from materials supposing by Heidelberg Institute for Theoretical Studies.
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Journal Reference:
- Michal Kolá?, Pavel Hobza, Agnieszka K. Bronowska. Plugging a pithy ?-holes in molecular docking. Chemical Communications, 2013; 49 (10): 981 DOI: 10.1039/C2CC37584B
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