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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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No Longer Whistling in the Dark: Scientists Uncover a Little-Understood Source of Waves Generated Throughout the Universe

Scientists at the U.S. Department of Energy's Princeton Plasma Physics Laboratory (PPPL) and other laboratories, using data from a NASA four-satellite mission that is studying reconnection, have developed a method for identifying the source of waves that help satellites determine their location in space.

New biofuel production system powered by a community of algae and fungi

MSU scientists have a new proof of concept for a biofuel production platform that uses two species of marine algae and soil fungi. It lowers cultivation and harvesting costs and increases productivity, factors that currently hold back biofuels from being widely adopted.

Multimodal Imaging Shows Strain Can Drive Chemistry in a Photovoltaic Material

A unique combination of imaging tools and atomic-level simulations has allowed a team led by the Department of Energy's Oak Ridge National Laboratory to solve a longstanding debate about the properties of a promising material that can harvest energy from light.

Study of tiny vortices could lead to new self-healing materials, other advances

Argonne scientists hope that tiny vortices, driven by various magnetic fields, will be able to move microscopic particles.

How a Molecular Signal Helps Plant Cells Decide When to Make Oil

Scientists identify new details of how a sugar-signaling molecule helps regulate oil production in plant cells. The work could point to new ways to engineer plants to produce substantial amounts of oil for use as biofuels or in the production of other oil-based products.

Neutrons Produce First Direct 3D Maps of Water During Cell Membrane Fusion

New 3D maps of water distribution during cellular membrane fusion could lead to new treatments for diseases associated with cell fusion. Using neutron diffraction at Oak Ridge National Laboratory, scientists made the first direct observations of water in lipid bilayers modeling cell membrane fusion.

Chemists Demonstrate Sustainable Approach to Carbon Dioxide Capture From Air

Chemists at Oak Ridge National Laboratory have demonstrated a practical, energy-efficient method of capturing carbon dioxide directly from air. If deployed at large scale and coupled to geologic storage, the technique may bolster the portfolio of responses to global climate change.

Nucleation a boon to sustainable nanomanufacturing

Young-Shin Jun, professor of energy, environmental & chemical engineering in the School of Engineering & Applied Science, and Quingun Li, a former doctoral student in her lab, are the first to measure the activation energy and kinetic factors of calcium carbonate's nucleation, both key to predicting and controlling the process.

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Scientists improve our understanding of the relationship between fundamental forces by re-creating the earliest moments of the universe.

Greater Than the Sum of Its Parts

Argonne scientists and their collaborators have developed a new model that merges basic electrochemical theory with theories used in different contexts, such as the study of photoelectrochemistry and semiconductor physics, to describe phenomena that occur in any electrode.


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Department of Energy Announces $218 Million for Quantum Information Science

The U.S. Department of Energy (DOE) announced $218 million in funding for 85 research awards in the important emerging field of Quantum Information Science (QIS).

Energy Secretary awards researchers for global threat reduction

Seven employees from the U.S. Department of Energy's (DOE) Argonne National Laboratory were among those presented with a Secretary of Energy Achievement Award at the Secretary's Honors Awards ceremony in Washington, D.C., on August 29.

University of Minnesota to lead $5.3 million federal grant to improve electronic circuit design

The University of Minnesota announced today that it has received a four-year, $5.3 million grant from the Defense Advanced Research Projects Agency (DARPA), an agency of the U.S. Department of Defense, to lead an effort that could spark the next wave of U.S. semiconductor innovation and broaden the competitive field for circuit design.

Berkeley Lab to Build an Advanced Quantum Computing Testbed

Lawrence Berkeley National Laboratory (Berkeley Lab) will receive $30 million over five years from the U.S. Department of Energy to build and operate an Advanced Quantum Testbed (AQT) allowing researchers to explore superconducting quantum processors to advance scientific research

Cheng wins Midwest Energy News' 40 Under 40 Award

Lei Cheng, an assistant chemist in the Materials Science division at the U.S. Department of Energy's (DOE) Argonne National Laboratory, has received a Midwest Energy News 40 Under 40 Award.

JCESR renewed for another five years

The U.S. Department of Energy (DOE) today announced its decision to renew the Joint Center for Energy Storage Research (JCESR), a DOE Energy Innovation Hub led by Argonne National Laboratory and focused on advancing battery science and technology.

Binghamton designated as NextFlex New York Node for flexible hybrid electronics initiative

NextFlex has designated Binghamton University to be the New York "Node" for its flexible hybrid electronics (FHE) initiative. As the NextFlex New York Node, Binghamton will design, develop and manufacture tools; process materials and products for flexible hybrid electronics; and attract, train and employ an advanced manufacturing workforce, building on the region's existing electronics manufacturing base.

First Particle Tracks Seen in Prototype for International Neutrino Experiment

The largest liquid-argon neutrino detector in the world has just recorded its first particle tracks, signaling the start of a new chapter in the story of the international Deep Underground Neutrino Experiment (DUNE). DUNE's scientific mission is dedicated to unlocking the mysteries of neutrinos, the most abundant (and most mysterious) matter particles in the universe.

Tais Gorkhover Wins LCLS Young Investigator Award for Pioneering Novel X-ray Imaging Methods

Tais Gorkhover, a principal investigator with the Stanford PULSE Institute, will receive the 2018 LCLS Young Investigator Award, granted to early-career scientists in recognition of exceptional research using the Linac Coherent Light Source (LCLS) X-ray free-electron laser at the Department of Energy's SLAC National Accelerator Laboratory.

ORNL, United Kingdom Lab Partner on Nuclear Energy Research

The United Kingdom's National Nuclear Laboratory and the U.S. Department of Energy's Oak Ridge National Laboratory have agreed to cooperate on a wide range of nuclear energy research and development efforts that leverage both organizations' unique expertise and capabilities.


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Breaking the Symmetry Between Fundamental Forces

Scientists improve our understanding of the relationship between fundamental forces by re-creating the earliest moments of the universe.

Water Plays Unexpected Role in Forming Minerals

Water molecules line up tiny particles to attach and form minerals; understanding how this happens impacts energy extraction and storage along with waste disposal.

Heavy Particles Get Caught Up in the Flow

First direct measurement show how heavy particles containing a charm quark get caught up in the flow of early universe particle soup.

Seeing Between the Atoms

New detector enables electron microscope imaging at record-breaking resolution.

Scaling Up Single-Crystal Graphene

New method can make films of atomically thin carbon that are over a foot long.

Discovered: Optimal Magnetic Fields Suppress Instabilities in Tokamak Plasmas

U.S. and Korean scientists show how to find and use beneficial 3-D field perturbations to stabilize dangerous edge-localized modes in plasma.

New Electron Glasses Sharpen Our View of Atomic-Scale Features

A new approach to atom probe tomography promises more precise and accurate measurements vital to semiconductors used in computers, lasers, detectors, and more.

Getting an Up-Close, 3-D View of Gold Nanostars

Scientists can now measure 3-D structures of tiny particles with properties that hold promise for advanced sensors and diagnostics.

Small, Short-Lived Drops of Early Universe Matter

Particle flow patterns suggest even small-scale collisions create drops of early universe quark-gluon plasma.

Tuning Terahertz Beams with Nanoparticles

Scientists uncover a way to control terahertz radiation using tiny engineered particles in a magnetic field, potentially opening the doors for better medical and environmental sensors.


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