SDSC Resources Used to Help Researchers Create New Drug Candidate That May Reduce Deficits in Parkinson’s Disease

October 7, 2016

Oct. 7 — An international team led by University of California San Diego researchers has employed a novel computational approach to design and create a new compound that in laboratory studies has reduced deficits and neurodegenerative symptoms that underlie Parkinson’s disease.

In a study published in the September 27 Advance Access issue of Brain, the researchers describe how their compound, dubbed NPT100-18A, prevents the binding and accumulation of alpha-synuclein or α-syn in neuronal membranes, now considered a hallmark of Parkinson’s disease and a related disorder called dementia with Lewy bodies.

“We’ve demonstrated a novel computational approach to design potential therapies for Parkinson’s disease and related disorders,” said the study’s co-first author Igor Tsigelny, a research scientist with the San Diego Supercomputer Center (SDSC) at UC San Diego, as well as the UC San Diego Moores Cancer Center and Department of Neurosciences.

Added Eliezer Masliah, the study’s principal investigator and former professor in UC San Diego School of Medicine’s Department of Neurosciences:  “It’s a first step, but we believe it’s a big step.”

Parkinson’s disease, which affects more than 10 million people worldwide, is characterized by impairment or deterioration of neurons in the area of the brain known as the substantia nigra. The disease typically occurs in people over the age of 60, with symptoms of shaking, rigidity, difficulty in walking, generally developing slowly over time and sometimes followed later by impairment in behavior and thought processes.

Since most symptoms of Parkinson’s disease are triggered by a lack of dopamine in the brain, many medications are aimed at either temporarily replenishing dopamine or mimicking the action of this brain chemical. Unfortunately, current drugs have only a limited impact on long-term neurological deficits and mortality.

For this reason, scientists have begun to focus their efforts on α-syn’s role in the disease, based largely on computer modeling describing how mutant forms of this protein penetrate and coil in cell membranes, and then aggregate in a matter of nanoseconds into dangerous ring structures that open pores to toxic ions that ultimately destroy neurons. The modeling has been supported by electron microscopy showing how damaged neurons in Parkinson’s patients are riddled with these ring structures.

Following this discovery in 2012, UC San Diego researchers began an intense search to identify drug candidates that could block the early formation of ring structures. Specifically, the researchers homed in on “hot spots” that block the binding of two α-syn proteins, or dimers.

“Our thinking was that disrupting the formation of membrane-embedded dimers at this early intervention point could reverse the effects of α-syn on synaptic function at a stage before irreversible neurodegenerative processes have been initiated,” said Masliah, now with the National Institutes of Health (NIH).

But the hunt proved highly complex, owing largely to the nature of the unstructured state of α-syn, sometimes referred to as a “chameleon” that constantly shifts its shape, somewhat like a slinky that’s bobbing and weaving on top of an earthquake epicenter.

“Our biggest hurdle was that α-syn doesn’t have any stable conformation,” said Tsigelny. “So long simulations were needed to define a huge set of possible conformations to find clusters of possible compounds that would work.”

Enter several supercomputers – including Trestles, Gordon, and the Triton Shared Computing Cluster, all based at SDSC; and Blue Gene, with the Argonne National Laboratory – that performed molecular dynamic simulations of in silico structures that would displace α-syn from cell membranes.

Based on these simulations, other members of the research team, including Wolfgang Wrasidlo, executive director of medicinal chemistry at Neuropore Therapeutics in San Diego, synthesized a library of 34 potential compounds that targeted the “hot spot” where pairs of α-syn proteins bind, merge, and aggregate in the cell membrane, an early step in the formation of toxic rings and ultimate death of a neuron. Of these drug candidates, the researchers identified one compound – NPT100-18A – as the most promising.

“Essentially, this compound mimics the protein’s amino acids in the place where two α-synucleins come into contact, thus preventing the binding of the second protein,” said Wrasidlo, previously with UC San Diego Moores Cancer Center, and the study’s first author.

Subsequent electron microscopy imaging by researchers at the University of Vienna demonstrated that the new compound reduced the formation of α-syn clusters in cell membranes. Further studies with “transgenic” mouse models prone to Parkinson’s disease, both at UC San Diego and UCLA, concluded that the compound improved behavioral deficits and neurodegeneration. Within an hour after it was administered, imaging studies in these mice further showed that the compound reduced accumulation of α-syn in cortical synapses.

“Specifically targeting the α-synuclein structure that is stabilized in cell membranes also allows for a more specific molecularly targeted drug design,” added Masliah.

Though highly encouraging, the researchers caution that the compound needs to be refined before clinical trials can be launched in the future.

Also contributing to the study, titled “A De Novo Compound Targeting Alpha-Synuclein Improves Deficits in Models of Parkinson’s Disease,” were Edward Rockenstein, Simona Eleuteri, Valentina Kouznetsova, Brian Spencer, Paula Desplats, Tania Gonzalez-Ruelas, Margaritha Trejo, and Cassia Overk, all from UC San Diego; Garima Dutta, Chunni Zhu, and Marie-Francoise, all from UCLA; Thomas Schwartz, Karin Ledolter and Robert Konrat, all from the University of Vienna; Diana Price, Douglas Bonhaus, Amy Paulino and Dieter Meier, all from Neuropore, based in San Diego; Stefan Winter and Herbert Moessler, from EVER Neuropharma, based in Austria; and Age Skjevik, from the University of Bergen in Norway.

Funding for the research came from NIH grant AG18440, The Michael J. Fox Foundation for Parkinson’s Research, and Neuropore Therapies.

About SDSC 

As an Organized Research Unit of UC San Diego, SDSC is considered a leader in data-intensive computing and cyberinfrastructure, providing resources, services, and expertise to the national research community, including industry and academia. Cyberinfrastructure refers to an accessible, integrated network of computer-based resources and expertise, focused on accelerating scientific inquiry and discovery. SDSC supports hundreds of multidisciplinary programs spanning a wide variety of domains, from earth sciences and biology to astrophysics, bioinformatics, and health IT. SDSC’s Comet joins the Center’s data-intensive Gordon cluster, and are both part of the National Science Foundation’s XSEDE (Extreme Science and Engineering Discovery Environment) program.


Source: SDSC

Subscribe to HPCwire's Weekly Update!

Be the most informed person in the room! Stay ahead of the tech trends with industy updates delivered to you every week!

Graphcore Introduces Next-Gen Intelligence Processing Unit for AI Workloads

July 15, 2020

British hardware designer Graphcore, which emerged from stealth in 2016 to launch its first-generation Intelligence Processing Unit (IPU), has announced its next-generation IPU platform: the IPU-Machine M2000. With the n Read more…

By Oliver Peckham

heFFTe: Scaling FFT for Exascale

July 15, 2020

Exascale computing aspires to provide breakthrough solutions addressing today’s most critical challenges in scientific discovery, energy assurance, economic competitiveness, and national security. This has been the mai Read more…

By Jack Dongarra and Stanimire Tomov

There’s No Storage Like ATGC: Breakthrough Helps to Store ‘The Wizard of Oz’ in DNA

July 15, 2020

Even as storage density reaches new heights, many researchers have their eyes set on a paradigm shift in high-density information storage: storing data in the four nucleotides (A, T, G and C) that constitute DNA, a metho Read more…

By Oliver Peckham

Get a Grip: Intel Neuromorphic Chip Used to Give Robotics Arm a Sense of Touch

July 15, 2020

Moving neuromorphic technology from the laboratory into practice has proven slow-going. This week, National University of Singapore researchers moved the needle forward demonstrating an event-driven, visual-tactile perce Read more…

By John Russell

What’s New in HPC Research: Volcanoes, Mobile Games, Proteins & More

July 14, 2020

In this bimonthly feature, HPCwire highlights newly published research in the high-performance computing community and related domains. From parallel programming to exascale to quantum computing, the details are here. Read more…

By Oliver Peckham

AWS Solution Channel

INEOS TEAM UK Accelerates Boat Design for America’s Cup Using HPC on AWS

The America’s Cup Dream

The 36th America’s Cup race will be decided in Auckland, New Zealand in 2021. Like all the teams, INEOS TEAM UK will compete in a boat whose design will have followed guidelines set by race organizers to ensure the crew’s sailing skills are fully tested. Read more…

Intel® HPC + AI Pavilion

Supercomputing the Pandemic: Scientific Community Tackles COVID-19 from Multiple Perspectives

Since their inception, supercomputers have taken on the biggest, most complex, and most data-intensive computing challenges—from confirming Einstein’s theories about gravitational waves to predicting the impacts of climate change. Read more…

Joliot-Curie Supercomputer Used to Build First Full, High-Fidelity Aircraft Engine Simulation

July 14, 2020

When industrial designers plan the design of a new element of a vehicle’s propulsion or exterior, they typically use fluid dynamics to optimize airflow and increase the vehicle’s speed and efficiency. These fluid dyn Read more…

By Oliver Peckham

Graphcore Introduces Next-Gen Intelligence Processing Unit for AI Workloads

July 15, 2020

British hardware designer Graphcore, which emerged from stealth in 2016 to launch its first-generation Intelligence Processing Unit (IPU), has announced its nex Read more…

By Oliver Peckham

heFFTe: Scaling FFT for Exascale

July 15, 2020

Exascale computing aspires to provide breakthrough solutions addressing today’s most critical challenges in scientific discovery, energy assurance, economic c Read more…

By Jack Dongarra and Stanimire Tomov

Get a Grip: Intel Neuromorphic Chip Used to Give Robotics Arm a Sense of Touch

July 15, 2020

Moving neuromorphic technology from the laboratory into practice has proven slow-going. This week, National University of Singapore researchers moved the needle Read more…

By John Russell

Max Planck Society Begins Installation of Liquid-Cooled Supercomputer from Lenovo

July 9, 2020

Lenovo announced today that it is supplying a new high performance computer to the Max Planck Society, one of Germany's premier research organizations. Comprise Read more…

By Tiffany Trader

President’s Council Targets AI, Quantum, STEM; Recommends Spending Growth

July 9, 2020

Last week the President Council of Advisors on Science and Technology (PCAST) met (webinar) to review policy recommendations around three sub-committee reports: Read more…

By John Russell

Google Cloud Debuts 16-GPU Ampere A100 Instances

July 7, 2020

On the heels of the Nvidia’s Ampere A100 GPU launch in May, Google Cloud is announcing alpha availability of the A100 “Accelerator Optimized” VM A2 instance family on Google Compute Engine. The instances are powered by the HGX A100 16-GPU platform, which combines two HGX A100 8-GPU baseboards using... Read more…

By Tiffany Trader

Q&A: HLRS’s Bastian Koller Tackles HPC and Industry in Germany and Europe

July 6, 2020

In this exclusive interview for HPCwire – sadly not face to face – Steve Conway, senior advisor for Hyperion Research, talks with Dr.-Ing Bastian Koller about the state of HPC and its collaboration with Industry in Europe. Koller is a familiar figure in HPC. He is the managing director at High Performance Computing Center Stuttgart (HLRS) and also serves... Read more…

By Steve Conway, Hyperion

OpenPOWER Reboot – New Director, New Silicon Partners, Leveraging Linux Foundation Connections

July 2, 2020

Earlier this week the OpenPOWER Foundation announced the contribution of IBM’s A21 Power processor core design to the open source community. Roughly this time Read more…

By John Russell

Supercomputer Modeling Tests How COVID-19 Spreads in Grocery Stores

April 8, 2020

In the COVID-19 era, many people are treating simple activities like getting gas or groceries with caution as they try to heed social distancing mandates and protect their own health. Still, significant uncertainty surrounds the relative risk of different activities, and conflicting information is prevalent. A team of Finnish researchers set out to address some of these uncertainties by... Read more…

By Oliver Peckham

[email protected] Turns Its Massive Crowdsourced Computer Network Against COVID-19

March 16, 2020

For gamers, fighting against a global crisis is usually pure fantasy – but now, it’s looking more like a reality. As supercomputers around the world spin up Read more…

By Oliver Peckham

[email protected] Rallies a Legion of Computers Against the Coronavirus

March 24, 2020

Last week, we highlighted [email protected], a massive, crowdsourced computer network that has turned its resources against the coronavirus pandemic sweeping the globe – but [email protected] isn’t the only game in town. The internet is buzzing with crowdsourced computing... Read more…

By Oliver Peckham

Supercomputer Simulations Reveal the Fate of the Neanderthals

May 25, 2020

For hundreds of thousands of years, neanderthals roamed the planet, eventually (almost 50,000 years ago) giving way to homo sapiens, which quickly became the do Read more…

By Oliver Peckham

DoE Expands on Role of COVID-19 Supercomputing Consortium

March 25, 2020

After announcing the launch of the COVID-19 High Performance Computing Consortium on Sunday, the Department of Energy yesterday provided more details on its sco Read more…

By John Russell

Neocortex Will Be First-of-Its-Kind 800,000-Core AI Supercomputer

June 9, 2020

Pittsburgh Supercomputing Center (PSC - a joint research organization of Carnegie Mellon University and the University of Pittsburgh) has won a $5 million award Read more…

By Tiffany Trader

Honeywell’s Big Bet on Trapped Ion Quantum Computing

April 7, 2020

Honeywell doesn’t spring to mind when thinking of quantum computing pioneers, but a decade ago the high-tech conglomerate better known for its control systems waded deliberately into the then calmer quantum computing (QC) waters. Fast forward to March when Honeywell announced plans to introduce an ion trap-based quantum computer whose ‘performance’ would... Read more…

By John Russell

10nm, 7nm, 5nm…. Should the Chip Nanometer Metric Be Replaced?

June 1, 2020

The biggest cool factor in server chips is the nanometer. AMD beating Intel to a CPU built on a 7nm process node* – with 5nm and 3nm on the way – has been i Read more…

By Doug Black

Leading Solution Providers

Contributors

Nvidia’s Ampere A100 GPU: Up to 2.5X the HPC, 20X the AI

May 14, 2020

Nvidia's first Ampere-based graphics card, the A100 GPU, packs a whopping 54 billion transistors on 826mm2 of silicon, making it the world's largest seven-nanom Read more…

By Tiffany Trader

‘Billion Molecules Against COVID-19’ Challenge to Launch with Massive Supercomputing Support

April 22, 2020

Around the world, supercomputing centers have spun up and opened their doors for COVID-19 research in what may be the most unified supercomputing effort in hist Read more…

By Oliver Peckham

Australian Researchers Break All-Time Internet Speed Record

May 26, 2020

If you’ve been stuck at home for the last few months, you’ve probably become more attuned to the quality (or lack thereof) of your internet connection. Even Read more…

By Oliver Peckham

15 Slides on Programming Aurora and Exascale Systems

May 7, 2020

Sometime in 2021, Aurora, the first planned U.S. exascale system, is scheduled to be fired up at Argonne National Laboratory. Cray (now HPE) and Intel are the k Read more…

By John Russell

Summit Supercomputer is Already Making its Mark on Science

September 20, 2018

Summit, now the fastest supercomputer in the world, is quickly making its mark in science – five of the six finalists just announced for the prestigious 2018 Read more…

By John Russell

TACC Supercomputers Run Simulations Illuminating COVID-19, DNA Replication

March 19, 2020

As supercomputers around the world spin up to combat the coronavirus, the Texas Advanced Computing Center (TACC) is announcing results that may help to illumina Read more…

By Staff report

$100B Plan Submitted for Massive Remake and Expansion of NSF

May 27, 2020

Legislation to reshape, expand - and rename - the National Science Foundation has been submitted in both the U.S. House and Senate. The proposal, which seems to Read more…

By John Russell

John Martinis Reportedly Leaves Google Quantum Effort

April 21, 2020

John Martinis, who led Google’s quantum computing effort since establishing its quantum hardware group in 2014, has left Google after being moved into an advi Read more…

By John Russell

  • arrow
  • Click Here for More Headlines
  • arrow
Do NOT follow this link or you will be banned from the site!
Share This