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!

University of Chicago Researchers Generate First Computational Model of Entire SARS-CoV-2 Virus

January 15, 2021

Over the course of the last year, many detailed computational models of SARS-CoV-2 have been produced with the help of supercomputers, but those models have largely focused on critical elements of the virus, such as its Read more…

By Oliver Peckham

Pat Gelsinger Returns to Intel as CEO

January 14, 2021

The Intel board of directors has appointed a new CEO. Intel alum Pat Gelsinger is leaving his post as CEO of VMware to rejoin the company that he parted ways with 11 years ago. Gelsinger will succeed Bob Swan, who will remain CEO until Feb. 15. Gelsinger previously spent 30 years... Read more…

By Tiffany Trader

Roar Supercomputer to Support Naval Aircraft Research

January 14, 2021

One might not think “aircraft” when picturing the U.S. Navy, but the military branch actually has thousands of aircraft currently in service – and now, supercomputing will help future naval aircraft operate faster, Read more…

By Staff report

DOE and NOAA Extend Computing Partnership, Plan for New Supercomputer

January 14, 2021

The National Climate-Computing Research Center (NCRC), hosted by Oak Ridge National Laboratory (ORNL), has been supporting the climate research of the National Oceanic and Atmospheric Administration (NOAA) for the last 1 Read more…

By Oliver Peckham

Using Micro-Combs, Researchers Demonstrate World’s Fastest Optical Neuromorphic Processor for AI

January 13, 2021

Neuromorphic computing, which uses chips that mimic the behavior of the human brain using virtual “neurons,” is growing in popularity thanks to high-profile efforts from Intel and others. Now, a team of researchers l Read more…

By Oliver Peckham

AWS Solution Channel

Now Available – Amazon EC2 C6gn Instances with 100 Gbps Networking

Amazon EC2 C6gn instances powered by AWS Graviton2 processors are now available!

Compared to C6g instances, this new instance type provides 4x higher network bandwidth, 4x higher packet processing performance, and 2x higher EBS bandwidth. Read more…

Intel® HPC + AI Pavilion

Intel Keynote Address

Intel is the foundation of HPC – from the workstation to the cloud to the backbone of the Top500. At SC20, Intel’s Trish Damkroger, VP and GM of high performance computing, addresses the audience to show how Intel and its partners are building the future of HPC today, through hardware and software technologies that accelerate the broad deployment of advanced HPC systems. Read more…

Honing In on AI, US Launches National Artificial Intelligence Initiative Office

January 13, 2021

To drive American leadership in the field of AI into the future, the National Artificial Intelligence Initiative Office has been launched by the White House Office of Science and Technology Policy (OSTP). The new agen Read more…

By Todd R. Weiss

Pat Gelsinger Returns to Intel as CEO

January 14, 2021

The Intel board of directors has appointed a new CEO. Intel alum Pat Gelsinger is leaving his post as CEO of VMware to rejoin the company that he parted ways with 11 years ago. Gelsinger will succeed Bob Swan, who will remain CEO until Feb. 15. Gelsinger previously spent 30 years... Read more…

By Tiffany Trader

Julia Update: Adoption Keeps Climbing; Is It a Python Challenger?

January 13, 2021

The rapid adoption of Julia, the open source, high level programing language with roots at MIT, shows no sign of slowing according to data from Julialang.org. I Read more…

By John Russell

Intel ‘Ice Lake’ Server Chips in Production, Set for Volume Ramp This Quarter

January 12, 2021

Intel Corp. used this week’s virtual CES 2021 event to reassert its dominance of the datacenter with the formal roll out of its next-generation server chip, the 10nm Xeon Scalable processor that targets AI and HPC workloads. The third-generation “Ice Lake” family... Read more…

By George Leopold

Researchers Say It Won’t Be Possible to Control Superintelligent AI

January 11, 2021

Worries about out-of-control AI aren’t new. Many prominent figures have suggested caution when unleashing AI. One quote that keeps cropping up is (roughly) th Read more…

By John Russell

AMD Files Patent on New GPU Chiplet Approach

January 5, 2021

Advanced Micro Devices is accelerating the GPU chiplet race with the release of a U.S. patent application for a device that incorporates high-bandwidth intercon Read more…

By George Leopold

Programming the Soon-to-Be World’s Fastest Supercomputer, Frontier

January 5, 2021

What’s it like designing an app for the world’s fastest supercomputer, set to come online in the United States in 2021? The University of Delaware’s Sunita Chandrasekaran is leading an elite international team in just that task. Chandrasekaran, assistant professor of computer and information sciences, recently was named... Read more…

By Tracey Bryant

Intel Touts Optane Performance, Teases Next-gen “Crow Pass”

January 5, 2021

Competition to leverage new memory and storage hardware with new or improved software to create better storage/memory schemes has steadily gathered steam during Read more…

By John Russell

Farewell 2020: Bleak, Yes. But a Lot of Good Happened Too

December 30, 2020

Here on the cusp of the new year, the catchphrase ‘2020 hindsight’ has a distinctly different feel. Good riddance, yes. But also proof of science’s power Read more…

By John Russell

Esperanto Unveils ML Chip with Nearly 1,100 RISC-V Cores

December 8, 2020

At the RISC-V Summit today, Art Swift, CEO of Esperanto Technologies, announced a new, RISC-V based chip aimed at machine learning and containing nearly 1,100 low-power cores based on the open-source RISC-V architecture. Esperanto Technologies, headquartered in... Read more…

By Oliver Peckham

Azure Scaled to Record 86,400 Cores for Molecular Dynamics

November 20, 2020

A new record for HPC scaling on the public cloud has been achieved on Microsoft Azure. Led by Dr. Jer-Ming Chia, the cloud provider partnered with the Beckman I Read more…

By Oliver Peckham

NICS Unleashes ‘Kraken’ Supercomputer

April 4, 2008

A Cray XT4 supercomputer, dubbed Kraken, is scheduled to come online in mid-summer at the National Institute for Computational Sciences (NICS). The soon-to-be petascale system, and the resulting NICS organization, are the result of an NSF Track II award of $65 million to the University of Tennessee and its partners to provide next-generation supercomputing for the nation's science community. Read more…

Is the Nvidia A100 GPU Performance Worth a Hardware Upgrade?

October 16, 2020

Over the last decade, accelerators have seen an increasing rate of adoption in high-performance computing (HPC) platforms, and in the June 2020 Top500 list, eig Read more…

By Hartwig Anzt, Ahmad Abdelfattah and Jack Dongarra

Aurora’s Troubles Move Frontier into Pole Exascale Position

October 1, 2020

Intel’s 7nm node delay has raised questions about the status of the Aurora supercomputer that was scheduled to be stood up at Argonne National Laboratory next year. Aurora was in the running to be the United States’ first exascale supercomputer although it was on a contemporaneous timeline with... Read more…

By Tiffany Trader

Julia Update: Adoption Keeps Climbing; Is It a Python Challenger?

January 13, 2021

The rapid adoption of Julia, the open source, high level programing language with roots at MIT, shows no sign of slowing according to data from Julialang.org. I 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

Programming the Soon-to-Be World’s Fastest Supercomputer, Frontier

January 5, 2021

What’s it like designing an app for the world’s fastest supercomputer, set to come online in the United States in 2021? The University of Delaware’s Sunita Chandrasekaran is leading an elite international team in just that task. Chandrasekaran, assistant professor of computer and information sciences, recently was named... Read more…

By Tracey Bryant

Leading Solution Providers

Contributors

Top500: Fugaku Keeps Crown, Nvidia’s Selene Climbs to #5

November 16, 2020

With the publication of the 56th Top500 list today from SC20's virtual proceedings, Japan's Fugaku supercomputer – now fully deployed – notches another win, Read more…

By Tiffany Trader

Texas A&M Announces Flagship ‘Grace’ Supercomputer

November 9, 2020

Texas A&M University has announced its next flagship system: Grace. The new supercomputer, named for legendary programming pioneer Grace Hopper, is replacing the Ada system (itself named for mathematician Ada Lovelace) as the primary workhorse for Texas A&M’s High Performance Research Computing (HPRC). Read more…

By Oliver Peckham

At Oak Ridge, ‘End of Life’ Sometimes Isn’t

October 31, 2020

Sometimes, the old dog actually does go live on a farm. HPC systems are often cursed with short lifespans, as they are continually supplanted by the latest and Read more…

By Oliver Peckham

Nvidia and EuroHPC Team for Four Supercomputers, Including Massive ‘Leonardo’ System

October 15, 2020

The EuroHPC Joint Undertaking (JU) serves as Europe’s concerted supercomputing play, currently comprising 32 member states and billions of euros in funding. I Read more…

By Oliver Peckham

Gordon Bell Special Prize Goes to Massive SARS-CoV-2 Simulations

November 19, 2020

2020 has proven a harrowing year – but it has produced remarkable heroes. To that end, this year, the Association for Computing Machinery (ACM) introduced the Read more…

By Oliver Peckham

Nvidia-Arm Deal a Boon for RISC-V?

October 26, 2020

The $40 billion blockbuster acquisition deal that will bring chipmaker Arm into the Nvidia corporate family could provide a boost for the competing RISC-V architecture. As regulators in the U.S., China and the European Union begin scrutinizing the impact of the blockbuster deal on semiconductor industry competition and innovation, the deal has at the very least... Read more…

By George Leopold

Intel Xe-HP GPU Deployed for Aurora Exascale Development

November 17, 2020

At SC20, Intel announced that it is making its Xe-HP high performance discrete GPUs available to early access developers. Notably, the new chips have been deplo Read more…

By Tiffany Trader

HPE, AMD and EuroHPC Partner for Pre-Exascale LUMI Supercomputer

October 21, 2020

Not even a week after Nvidia announced that it would be providing hardware for the first four of the eight planned EuroHPC systems, HPE and AMD are announcing a Read more…

By Oliver Peckham

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