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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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Carbon Nanotube Optics Poised to Provide Pathway to Optical-Based Quantum Cryptography and Quantum Computing

Researchers at Los Alamos and partners in France and Germany are exploring the enhanced potential of carbon nanotubes as single-photon emitters for quantum information processing. Their analysis of progress in the field is published in this week's edition of the journal Nature Materials.

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Scientists Use Neutrons to Take a Deeper Look at Record Boost in Thermoelectric Efficiency

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The science behind pickled battery electrolytes

Argonne material scientists have discovered a reaction that helps explain the behavior of a key electrolyte additive used to boost battery performance.

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Researchers at the Department of Energy's Joint BioEnergy Institute (JBEI) based at Berkeley Lab have pioneered a new way to synthesize DNA sequences through a creative use of enzymes that promises to be faster, cheaper, and more accurate. DNA synthesis is a fundamental tool in the rapidly growing field of synthetic biology, in which organisms can be engineered to do things like decompose plastic and manufacture biofuels and medicines. This discovery could dramatically accelerate the pace of scientific discovery.

Scientists Create Continuously Emitting Microlasers With Nanoparticle-Coated Beads

Researchers have found a way to convert nanoparticle-coated microscopic beads into lasers smaller than red blood cells. These microlasers, which convert infrared light into light at higher frequencies, are among the smallest continuously emitting lasers of their kind ever reported and can constantly and stably emit light for hours at a time, even when submerged in biological fluids such as blood serum.

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A diverse mix of species improves the stability and fuel-oil yield of algal biofuel systems, as well as their resistance to invasion by outsiders, according to the findings of a federally funded outdoor study by University of Michigan researchers.

SLAC, Stanford Scientists Discover How a Hardy Microbe's Crystalline Shell Helps it Reel in Food

SLAC and Stanford scientists have discovered how some archaea thrive where other organisms would starve: Their crystalline shells not only protect them from the environment, but they also draw in nutrients through nanosized pores. Those nutrients concentrate in the space between the shell and the microbial cell, so what looks like a famine turns into a feast.

Scientists Make the First Molecular Movie of One of Nature's Most Widely Used Light Sensors

Scientists have made the first molecular movie of the instant when light hits a sensor that's widely used in nature for probing the environment and harvesting energy from light. The sensor, a form of vitamin A known as retinal, is central to a number of important light-driven processes in people, animals, microbes and algae, including human vision and some forms of photosynthesis, and the movie shows it changing shape in a trillionth of an eye blink.


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Professor Emily Liu Receives $1.8 Million DoE Award for Solar Power Systems Research

Li (Emily) Liu, associate professor of nuclear engineering and engineering physics in the Department of Mechanical, Aerospace, and Nuclear Engineering at Rensselaer Polytechnic Institute, has been selected by the U.S. Department of Energy Solar Energy Technologies Office (SETO) to receive a $1.8 million award to study high-temperature molten-salt properties and corrosion mechanisms.

Vasilis Fthenakis Receives IEEE's William R. Cherry Award

UPTON, NY; Vasilis Fthenakis, a Senior Scientist Emeritus at the U.S. Department of Energy's (DOE) Brookhaven National Laboratory and Founder and Director of the Center for Life Cycle Analysis at Columbia University, will receive the 2018 William R. Cherry Award from the Institute of Electrical & Electronics Engineers (IEEE).

New PPPL director Steve Cowley is honored with knighthood by Queen Elizabeth II

Steven Cowley, newly named director of the U.S. Department of Energy's (DOE) Princeton Plasma Physics Laboratory (PPPL) effective July 1, has received a knighthood from Queen Elizabeth "for services to science and the development of nuclear fusion."

UVA Darden Releases Policy Playbook Identifying Six Actions to Catalyze Clean-Tech Innovation

Moving the needle on climate change will require substantive and disruptive innovation across multiple industry sectors. Public and private investment focused on a few key areas could have a significant impact, according to a new policy playbook released by the Batten Institute for Entrepreneurship and Innovation on 8 June.

Work Begins on New SLAC Facility for Revolutionary Accelerator Science

The Department of Energy's SLAC National Accelerator Laboratory has started to assemble a new facility for revolutionary accelerator technologies that could make future accelerators 100 to 1,000 times smaller and boost their capabilities.

Oak Ridge National Laboratory Launches America's New Top Supercomputer for Science

The U.S. Department of Energy's Oak Ridge National Laboratory unveiled Summit as the world's most powerful and smartest scientific supercomputer.

Takeuchi Receives European Inventor Award 2018 in the Non-EPO Countries Category

Prolific patent-holder won for inventing battery that increases the lifespan of implantable defibrillators fivefold, greatly reducing need for reoccurring surgery

Steve Kevan Named Next Director of Berkeley Lab's Advanced Light Source

After an international search, Stephen D. "Steve" Kevan has been named the new director of the Advanced Light Source (ALS) at the U.S. Department of Energy's Lawrence Berkeley National Laboratory.

International corrosion society elects first Sandia fellow

Sandia National Laboratories materials scientist David Enos has been elected a fellow of NACE International, the chief professional society for corrosion engineering. He is the first Sandia employee to receive the honor.

Power to the People

The University of Utah College of Engineering has received a $2 million grant to create a laboratory and develop new technology for communities with backup power sources, known as microgrids, so they can quickly and more securely operate in the event of a massive power outage due to a natural disaster or cyberattack.


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New Tech Uses Isomeric Beams to Study How and Where the Galaxy Makes One of Its Most Common Elements

A new measurement using a beam of aluminum-26 prepared in a metastable state allows researchers to better understand the creation of the elements in our galaxy.

Simulations of Magnetically Confined Plasmas Reveal a Self-Regulating Stabilizing Mechanism

A mysterious mechanism that prevents instabilities may be similar to the process that maintains the Earth's magnetic field.

Seeing All the Colors of the Plasma Wind

2-D velocity imaging helps fusion researchers understand the role of ion winds (aka flows) in the boundary of tokamak plasmas.

Renewable Solvents Derived From Lignin Lowers Waste in Biofuel Production

New class of solvents breaks down plant biomass into sugars for biofuels and bioproducts in a closed-loop biorefinery concept.

Scientists Studying Nuclear Spin Make a Surprising Discovery

The size of a nucleus appears to influence the direction of certain particles emitted from collisions with spinning protons.

Simulating Turbulent Bubbly Flows in Nuclear Reactors

With a better understanding of bubbly flows, researchers can improve the safety and operation of our nuclear reactors.

Solving a Magnesium Mystery in Rechargeable Battery Performance

Study reveals surprising, bad chemical reactivity in battery components previously considered compatible.

Changing the Surroundings Improves Catalysis

Water changes how cobalt-based molecule turns carbon dioxide into chemical feedstock.

How to Draw a Line Narrower Than a Cold Virus

Scientists use ion beams to write high-purity metal structures, enabling nanofabrication opportunities.

Powering Up With a Smart Window

Window material repeatedly switches from being see-through to blocking the heat and converting sunlight into electricity.


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