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Neutrons’ view of hydrogen yields insight into HIV drug design

ORNL-led study demonstrates relevance of neutrons in biomedical research

 

An ORNL-led team used neutrons to study the interactions between HIV protease, a protein produced by the HIV virus, and an antiviral drug called amprenavir commonly used to block virus replication. The magenta mesh is the neutron scattering density map showing the exact locations of hydrogen atoms bound to oxygen atoms. The blue dashed lines represent the strongest hydrogen bonds between the drug and the enzyme. This knowledge will help researchers improve the drug’s chemistry and increase its effectiveness. An ORNL-led team used neutrons to study the interactions between HIV protease, a protein produced by the HIV virus, and an antiviral drug called amprenavir commonly used to block virus replication. The magenta mesh is the neutron scattering density map showing the exact locations of hydrogen atoms bound to oxygen atoms. The blue dashed lines represent the strongest hydrogen bonds between the drug and the enzyme. This knowledge will help researchers improve the drug’s chemistry and increase its effectiveness. (hi-res image)

A new study from an international team led by the Department of Energy’s Oak Ridge National Laboratory is guiding drug designers toward improved pharmaceuticals to treat HIV. The scientists used neutrons and x-rays to study the interactions between HIV protease, a protein produced by the HIV virus, and an antiviral drug commonly used to block virus replication.

Using neutrons from the Institut Laue-Langevin in Grenoble, France, the researchers gained a never-before-seen view of hydrogen bonds that connect the HIV protease and the drug. Unlike x-rays, neutrons can easily detect the position of hydrogen atoms.  

“Knowing where hydrogen atoms are located gives researchers a much better idea about the nature and strength of the interactions,” said lead author Andrey Kovalevsky of ORNL. “By applying neutron crystallography we have effectively increased the clarity of this picture, because hydrogen atoms become visible in the neutron structures. Using neutrons, we are now able to see every atom in a protein-drug complex, all the way to the smallest atom in nature.”

The research, published in the Journal of Medicinal Chemistry, presents drug designers with a set of new potential sites for the improvement of the drug’s surface chemistry to significantly strengthen the binding, thereby increasing the effectiveness of the drugs and reducing the necessary dosages.

Several new instruments suited to the study of proteins are scheduled come online over the next year at ORNL’s two neutron facilities -- the Spallation Neutron Source and the High Flux Isotope Reactor. Kovalevsky, an instrument scientist for one of the new ORNL instruments, anticipates that the additional capacity for studying protein crystals with neutrons will enable more advances in biomedical research like the HIV protease study.

“We are confident that by combining the two crystallographic techniques -- x-rays and neutrons -- it will be possible to significantly improve the method of structure-guided drug design,” he said. “This research could ultimately provide patients with newer more effective medicines to not only battle HIV infection, but for other diseases as well.”  

Read more about the study in the ILL press release. The research team included scientists from ORNL, Georgia State University, Purdue University and Harwell Oxford in Great Britain.

 -  Morgan McCorkle,  865.574.7308,  August 13, 2013
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