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The DOE Science News Source is a Newswise initiative to promote research news from the Office of Science of the DOE to the public and news media.
  • 2018-02-12 13:05:43
  • Article ID: 689374

Neutron Study of Glaucoma Drugs Offers Clues About Enzyme Targets for Aggressive Cancers

  • Credit: (ORNL/Andrey Kovalevsky)

    This image shows the active site of hCA II. The active site is flanked by hydrophilic (violet) and hydrophobic (green) binding pockets that can be used to design specific drugs targeting cancer-associated hCAs. Five clinical drugs are shown superimposed in the hCA II active site, based on room-temperature neutron structures.

  • Credit: (ORNL/Andrey Kovalevsky)

    Three-dimensional structures of the clinical drugs brinzolamide (BZM, left) and dorzolamide (DZM, right) as observed in the hCA II active site. The red arrow shows the amino groups of the drugs: in BZM, the nitrogen atom (in blue) is not protonated and thus not charged; in DZM, the nitrogen atom has accepted an extra proton and thus is positively charged.

OAK RIDGE, Tenn., Feb. 12, 2018 – New insights from neutron analysis of glaucoma drugs and their enzyme target may help scientists design drugs that more effectively target aggressive cancers.  

A team of researchers led by the Department of Energy’s Oak Ridge National Laboratory used neutron macromolecular crystallography to investigate the different states of three glaucoma drugs as they interact with the targeted enzyme, human carbonic anhydrase II (hCA II).

“Our goal was to observe differences in the presentation of three clinically used glaucoma drugs while they are bound to the hCA II enzyme,” said Andrey Kovalevsky, an instrument scientist at ORNL and a senior co-author of the study. “By looking at how well these drugs target hCA II in protonated, neutral and deprotonated states, we hoped to obtain insights that would make it possible to improve these medicines so they can better target enzymes linked to cancer.”

Protonation refers to the presence, addition or loss of a proton, which gives the drug a neutral, positive or negative charge, respectively. Altering a drug’s charge could change its ability to recognize and bind with its target protein and consequently, its effectiveness.

The study, published in the journal Structure, found that temperature, pH, and the electrical charge of the three glaucoma drugs affected their ability to target and bind with the hCA II enzyme.

“This discovery was really a proof of principle for us,” said Robert McKenna, a professor at the University of Florida and a senior co-author of the study. “It opened our eyes to how changes in temperature and pH can impact the protonation state of the drug, which in turn makes it more or less effective.”

New information about the hydrogen-bonding networks that make up the active site of hCA II may help other scientists develop new and better drugs for cancer treatment. The family of hCA enzymes contains similar proteins, such as hCA IX and XII, that are associated with aggressive breast cancers, such as triple negative breast cancer.

“We want to exploit the difference in charge, pH and temperature to see if we can design drugs that are more effective at targeting these enzymes,” said Kovalevsky. “If we can understand binding at the atomic level, we can redesign drugs and turn them into stronger and more selective ‘magnets’ that will be attracted to cancer-associated enzymes. Such drugs would be much more effective at killing cancer cells while leaving healthy cells unhurt, which significantly reduces side effects for patients.”

Many scientists have used X-ray crystallography to analyze the structures of hCA enymes, but these studies lack complete atomic information on drug binding because of X-rays’ inability to visualize hydrogen atoms abundant in proteins and enzymes.

Neutrons are sensitive to lighter elements, so they provide much more detailed information on the location of hydrogen atoms. Seeing hydrogen is critical to studying protonation states of an enzyme and ligand—a molecule that binds to a biological macromolecule—and to analyzing the architecture of hydrogen-bonding networks. Neutrons also offer other experimental advantages.

“When you use neutron diffraction you don’t have radiation damage, so you can do your study at room temperature,” said McKenna. “In addition, freezing crystals may alter the drug and enzyme, introducing a false view into the study, while room temperature studies more closely resemble the environment the drug will be used in.”

Along with Kovalevsky, the paper’s coauthors include Hector Velazquez, Matthew J. Cuneo and Kevin L. Weiss of ORNL; Mayank Aggarwal of ORNL and the Shull Wollen Center; Jeremy C. Smith of the University of Tennessee and ORNL; Matthew P. Blakeley of the Institute Laue-Langevin; S. Zoë Fisher of the European Spallation Source and Lund University; and Robert McKenna of the University of Florida.

The research was funded in part by the ORNL Shull Fellowship held by Mayank Aggarwal. Neutron crystallography was performed on the MaNDi instrument at the Spallation Neutron Source, a DOE Office of Science User Facility, and on the LADI-III instrument at the Institut Laue Langevin. 

ORNL is managed by UT-Battelle for DOE’s Office of Science. The Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time. For more information, please visit http://science.energy.gov/.

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In a First, Tiny Diamond Anvils Trigger Chemical Reactions by Squeezing

Menlo Park, Calif. --Scientists have turned the smallest possible bits of diamond and other super-hard specks into "molecular anvils" that squeeze and twist molecules until chemical bonds break and atoms exchange electrons. These are the first such chemical reactions triggered by mechanical pressure alone, and researchers say the method offers a new way to do chemistry at the molecular level that is greener, more efficient and much more precise.

Berkeley Lab "Minimalist Machine Learning" Algorithms Analyze Images From Very Little Data

Berkeley Lab mathematicians have developed a new approach to machine learning aimed at experimental imaging data. Rather than relying on the tens or hundreds of thousands of images used by typical machine learning methods, this new approach "learns" much more quickly and requires far fewer images.

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Electric Eel-Inspired Device Reaches 110 Volts

In an effort to create a power source for future implantable technologies, a team of researchers developed an electric eel-inspired device that produced 110 volts from gels filled with water, called hydrogels. Their results show potential for a soft power source to draw on a biological system's chemical energy. Anirvan Guha will present the research during the 62nd Biophysical Society Annual Meeting, Feb. 17-21.


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ORNL Wins Four FLC Technology Transfer Awards

Four technologies developed at the Department of Energy's Oak Ridge National Laboratory have earned 2018 Excellence in Technology Transfer Awards from the Federal Laboratory Consortium for Technology Transfer (FLC).

Pacific Northwest National Laboratory, OHSU Create Joint Research Co-Laboratory to Advance Precision Medicine

News Release PORTLAND, Ore. -- Pacific Northwest National Laboratory and OHSU today announced a joint collaboration to improve patient care by focusing research on highly complex sets of biomedical data, and the tools to interpret them.The OHSU-PNNL Precision Medicine Innovation Co-Laboratory, called PMedIC, will provide a comprehensive ecosystem for scientists to utilize integrated 'omics, data science and imaging technologies in their research in order to advance precision medicine -- an approach to disease treatment that takes into account individual variability in genes, environment and lifestyle for each person.

The Mysteries of Plasma and Solar Eruptions Earn PPPL Graduate an Astrophysics Prize

Article describes dissertation award for graduate of Princeton University Department of Astrophysical Sciences.

45-Year-Old Telescope Gets a Makeover to Demystify Dark Energy

Forty-five years ago this month, a telescope tucked inside a 14-story, 500-ton dome atop a mile-high peak in Arizona took in the night sky for the first time and recorded its observations on glass photographic plates. Today, the dome closes on the previous science chapters of the 4-meter Nicholas U. Mayall Telescope and starts preparing for its new role in creating the largest 3-D map of the universe. This map could help determine why the universe is expanding at faster and faster rates, driven by an unknown force called dark energy.

MSU Uses $3 Million NASA Grant to Find Better Ways to Regulate Dams

Michigan State University researchers, equipped with $3 million from NASA, will investigate innovative methods to improve dams so that they are less harmful to people and the environment.

Harker School Wins Second Consecutive SLAC Regional DOE Science Bowl

Twenty-four teams from 16 Bay Area high schools faced off Feb. 3 in the SLAC Regional DOE Science Bowl, a series of fast-paced question-and-answer matches that test knowledge in biology, chemistry, physics, earth and space sciences, energy and math. The competition is hosted annually by the Department of Energy's SLAC National Accelerator Laboratory.

David Asner Named Deputy Associate Laboratory Director and Head of the Instrumentation Division in Brookhaven Lab's Nuclear and Particle Physics Directorate

A particle physicist with extensive leadership and management experience, Asner will help expand a portfolio of physics programs and oversee instrumentation research and development.

UIC to Provide Energy-Saving 'Kits' with $3.1m in Funding From ComEd

The University of Illinois at Chicago's Energy Resources Center has received funding from ComEd to provide energy-efficient LED light bulbs, advanced power strips, and educational material to income-qualified participants in northern Illinois.As part of a $3.1 million year-long investment, the utility company will fund the Low Income Kit Energy (LIKE) program, allowing engineers at UIC's Energy Resources Center to provide energy-saving kits to 35,000 eligible individuals and/or families.

DOE's HPC4Manufacturing Program Seeks Industry Proposals

The Department of Energy (DOE) on Feb. 1 announced up to $3 million will be made available to U.S. manufacturers for public/private projects aimed at applying high performance computing to industry challenges for the advancement of energy innovation.

Elke-Caroline Aschenauer Awarded Prestigious Humboldt Research Award

UPTON, NY -- Elke-Caroline Aschenauer, a senior physicist at the U.S. Department of Energy's Brookhaven National Laboratory, has been awarded a Humboldt Research Award for her contributions to the field of experimental nuclear physics. This prestigious international award--issued by the Alexander von Humboldt Foundation in Bonn, Germany--comes with a prize of EUR60,000 (more than $70,000 U.


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Tuning Quantum Light Sources

First known material capable of emitting single photons at room temperature and telecom wavelengths.

Working Night and Day

Day-night changes in light and temperature power a low-cost material assembly that mimics biological self-copying.

A Nanowire Array to Screen Drugs for Neurodegenerative Diseases

Engineers develop wires that penetrate neurons and measure their activity

Squeezing Into the Best Shape

Gel uses nanoparticles for on-demand control of droplet shapes, of interest for energy storage and catalysis.

Forcing the Hand of Elusive Electrons

Current generated when light hits a material reveals electrons behaving like an elusive particle.

Single Atoms in Nano-Cages

Tiny cages can trap and release inert argon gas atoms, allowing their further study and providing a new way to capture rare gases.

Unwavering Juggler with Three Extra Electrons

Simulations discovered the first molecule with three extra electrons and extraordinary stability.

Deep Dive Into How Electrons Behave

Unprecedented characterization of subsurface electronic states could lead to better semiconductors and seeing new interactions.

How Bacteria Produce Manganese Oxide Nanoparticles

Multiple techniques to characterize an enzyme complex shed light on how bacteria create particles and contribute to global cycles.

Meet the Director: Sergei Nagaitsev

This is one in a series of profiles on directors of the SC-stewarded user facilities. This profile features Sergei Nagaitsev, director of the Fermilab Accelerator Complex.


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