Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

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

18.01.2013
Halogen bonding has been applied in crystal engineering, materials research, and nanotechnology for some time. Scientists from the Heidelberg Institute for Theoretical Studies (HITS) and the Czech Academy of Science in Prague have now developed a new tool to use halogen bonds for drug discovery applications.

Halogen chemistry has been exploited by medicinal chemists for nearly 70 years. To date, halogens were regarded useful for optimization 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.


Left panel: the charge distribution around the bromobenzene molecule. The regions of negative electrostatic potential are in blue, positive regions in grey. The grey disc in the forefront represents the ?-hole. Right panel: the overlay of the predicted binding poses of K17 inhibitor of casein kinase 2 (PDB code 2OXY) with (red) and without (blue) explicit sigma-holes (ESH) and comparison with the crystal structure (grey).
Image: Agnieszka Bronowska / HITS

In short: They make compounds of interest more drug-like. However, direct interactions mediated by halogen atoms have been much ignored in pre-clinical drug development.

Recently, scientists from Heidelberg and Prague, working in quantum chemistry and structure-based drug design, have developed a new tool for the usage of halogen bonds for computational medicinal chemistry and drug discovery applications. The study, led by Dr. Agnieszka Bronowska from the Heidelberg Institute for Theoretical Studies (HITS) and conducted in cooperation with scientists from the Czech Academy of Sciences, has been published in Chemical Communication.
Most halogens - except fluorine - have unique properties which allow them to stabilize 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 the directional and stabilizing character of halogen bonding 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 thus to failure in drug development.

By approximating the positively charged sigma-hole with a massless, charged pseudo-atom (denoted as explicit sigma-hole or ESH), Agnieszka Bronowska and her colleagues incorporated a quantum-chemical effect into faster (and much less accurate) computational methods applicable to structure-based drug design. “We tested nearly a hundred complexes between medicinally relevant proteins and halogenated molecules”, Bronowska says. “The results showed significant improvement in the description of such complexes upon introduction of ESH.”
The new method is already used by research groups in the Czech Republic, in the United Kingdom and in the U.S. for designing novel compounds to treat chemotherapy-resistant cancers, infectious diseases, and Alzheimer’s disease.

Scientific Publication:
Plugging the explicit sigma-holes in molecular docking. Michal Kolár, Pavel Hobza and Agnieszka K. Bronowska. Chem. Commun., 2013,49 (10), 981-983
DOI: 10.1039/C2CC37584B
http://pubs.rsc.org/en/content/articlelanding/2013/cc/c2cc37584b

Scientific Contact:
Dr. Agnieszka Bronowska
Molecular Biomechanics Group (MBM)
Heidelberg Institute for Theoretical Studies (HITS)
Agnieszka.bronowska@h-its.org
Press Contact:
Dr. Peter Saueressig
Public Relations
Heidelberg Institute for Theoretical Studies (HITS)
Phone: +49-6221-533245
Peter.saueressig@h-its.org

Dr. Peter Saueressig | idw
Further information:
http://www.h-its.org
http://www.h-its.org/english/press/pressreleases.php?we_objectID=944
http://pubs.rsc.org/en/content/articlelanding/2013/cc/c2cc37584b

More articles from Life Sciences:

nachricht Scientists coax proteins to form synthetic structures with method that mimics nature
15.01.2019 | University of Texas at Austin

nachricht DNA library of apoid wasps published
15.01.2019 | Staatliche Naturwissenschaftliche Sammlungen Bayerns

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Nanocellulose for novel implants: Ears from the 3D-printer

Cellulose obtained from wood has amazing material properties. Empa researchers are now equipping the biodegradable material with additional functionalities to produce implants for cartilage diseases using 3D printing.

It all starts with an ear. Empa researcher Michael Hausmann removes the object shaped like a human ear from the 3D printer and explains:

Im Focus: Elucidating the Atomic Mechanism of Superlubricity

The phenomenon of so-called superlubricity is known, but so far the explanation at the atomic level has been missing: for example, how does extremely low friction occur in bearings? Researchers from the Fraunhofer Institutes IWM and IWS jointly deciphered a universal mechanism of superlubricity for certain diamond-like carbon layers in combination with organic lubricants. Based on this knowledge, it is now possible to formulate design rules for supra lubricating layer-lubricant combinations. The results are presented in an article in Nature Communications, volume 10.

One of the most important prerequisites for sustainable and environmentally friendly mobility is minimizing friction. Research and industry have been dedicated...

Im Focus: Mission completed – EU partners successfully test new technologies for space robots in Morocco

Just in time for Christmas, a Mars-analogue mission in Morocco, coordinated by the Robotics Innovation Center of the German Research Center for Artificial Intelligence (DFKI) as part of the SRC project FACILITATORS, has been successfully completed. SRC, the Strategic Research Cluster on Space Robotics Technologies, is a program of the European Union to support research and development in space technologies. From mid-November to mid-December 2018, a team of more than 30 scientists from 11 countries tested technologies for future exploration of Mars and Moon in the desert of the Maghreb state.

Close to the border with Algeria, the Erfoud region in Morocco – known to tourists for its impressive sand dunes – offered ideal conditions for the four-week...

Im Focus: Programming light on a chip

Research opens doors in photonic quantum information processing, optical signal processing and microwave photonics

Researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have developed a new integrated photonics platform that can...

Im Focus: Physicists uncover new competing state of matter in superconducting material

A team of experimentalists at the U.S. Department of Energy's Ames Laboratory and theoreticians at University of Alabama Birmingham discovered a remarkably long-lived new state of matter in an iron pnictide superconductor, which reveals a laser-induced formation of collective behaviors that compete with superconductivity.

"Superconductivity is a strange state of matter, in which the pairing of electrons makes them move faster," said Jigang Wang, Ames Laboratory physicist and...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

11th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Aachen, 3-4 April 2019

14.01.2019 | Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

New Plastics Economy Investor Forum - Meeting Point for Innovations

10.12.2018 | Event News

 
Latest News

Scientists coax proteins to form synthetic structures with method that mimics nature

15.01.2019 | Life Sciences

Next generation photonic memory devices are light-written, ultrafast and energy efficient

15.01.2019 | Information Technology

Viennese scientists develop promising new type of polymers

15.01.2019 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>