Featured Research

from universities, journals, and other organizations

Small change for big improvement: Halogen bonds and drug discovery

Date:
January 18, 2013
Source:
Heidelberg Institute for Theoretical Studies
Summary:
Halogen bonding has been applied in crystal engineering, materials research, and nanotechnology for some time. Scientists have now developed a new tool to use halogen bonds for drug discovery applications.

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 sigma-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).
Credit: Agnieszka Bronowska / HITS

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. 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 (image, 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.


Story Source:

The above story is based on materials provided by Heidelberg Institute for Theoretical Studies. Note: Materials may be edited for content and length.


Journal Reference:

  1. Michal Kolář, Pavel Hobza, Agnieszka K. Bronowska. Plugging the explicit σ-holes in molecular docking. Chemical Communications, 2013; 49 (10): 981 DOI: 10.1039/C2CC37584B

Cite This Page:

Heidelberg Institute for Theoretical Studies. "Small change for big improvement: Halogen bonds and drug discovery." ScienceDaily. ScienceDaily, 18 January 2013. <www.sciencedaily.com/releases/2013/01/130118064729.htm>.
Heidelberg Institute for Theoretical Studies. (2013, January 18). Small change for big improvement: Halogen bonds and drug discovery. ScienceDaily. Retrieved September 1, 2014 from www.sciencedaily.com/releases/2013/01/130118064729.htm
Heidelberg Institute for Theoretical Studies. "Small change for big improvement: Halogen bonds and drug discovery." ScienceDaily. www.sciencedaily.com/releases/2013/01/130118064729.htm (accessed September 1, 2014).

Share This




More Health & Medicine News

Monday, September 1, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

We've Got Mites Living In Our Faces And So Do You

We've Got Mites Living In Our Faces And So Do You

Newsy (Aug. 30, 2014) — A new study suggests 100 percent of adult humans (those over 18 years of age) have Demodex mites living in their faces. Video provided by Newsy
Powered by NewsLook.com
Liberia Continues Fight Against Ebola

Liberia Continues Fight Against Ebola

AFP (Aug. 30, 2014) — Authorities in Liberia try to stem the spread of the Ebola epidemic by raising awareness and setting up sanitation units for people to wash their hands. Duration: 00:41 Video provided by AFP
Powered by NewsLook.com
California Passes 'yes-Means-Yes' Campus Sexual Assault Bill

California Passes 'yes-Means-Yes' Campus Sexual Assault Bill

Reuters - US Online Video (Aug. 30, 2014) — California lawmakers pass a bill requiring universities to adopt "affirmative consent" language in their definitions of consensual sex, part of a nationwide drive to curb sexual assault on campuses. Linda So reports. Video provided by Reuters
Powered by NewsLook.com
New Drug Could Reduce Cardiovascular Deaths

New Drug Could Reduce Cardiovascular Deaths

Newsy (Aug. 30, 2014) — The new drug from Novartis could reduce cardiovascular deaths by 20 percent compared to other similar drugs. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins