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!

Democratization of HPC Part 3: Ninth Graders Tap HPC in the Cloud to Design Flying Boats

October 18, 2018

This is the third in a series of articles demonstrating the growing acceptance of high-performance computing (HPC) in new user communities and application areas. In this article we present UberCloud use case #208 on how Read more…

By Wolfgang Gentzsch and Håkon Bull Hove

Penguin Computing Launches Consultancy for Piecing AI Strategies Together

October 18, 2018

AI stands before the HPC industry as a beacon of great expectations, yet market research repeatedly shows that AI adoption is commonly stuck in the talking phase, on the near side of a difficult chasm to cross. In respon Read more…

By Tiffany Trader

When Water Quality—Not Quantity—Hinders HPC Cooling

October 18, 2018

Attention has been paid to the sheer quantity of water consumed by supercomputers’ cooling towers – and rightly so, as they can require thousands of gallons per minute to cool. But in the background, another factor can emerge, bottlenecking efficiency and raising costs: water quality. Read more…

By Oliver Peckham

HPE Extreme Performance Solutions

One Small Step Toward Mars: One Giant Leap for Supercomputing

Since the days of the Space Race between the U.S. and the former Soviet Union, we have continually sought ways to perform experiments in space. Read more…

IBM Accelerated Insights

Paper Offers ‘Proof’ of Quantum Advantage on Some Problems

October 18, 2018

Is quantum computing worth all the effort being poured into it or should we just wait for classical computing to catch up? An IBM blog today posed those questions and, you won’t be surprised, offers a firm “it’s wo Read more…

By John Russell

Penguin Computing Launches Consultancy for Piecing AI Strategies Together

October 18, 2018

AI stands before the HPC industry as a beacon of great expectations, yet market research repeatedly shows that AI adoption is commonly stuck in the talking phas Read more…

By Tiffany Trader

When Water Quality—Not Quantity—Hinders HPC Cooling

October 18, 2018

Attention has been paid to the sheer quantity of water consumed by supercomputers’ cooling towers – and rightly so, as they can require thousands of gallons per minute to cool. But in the background, another factor can emerge, bottlenecking efficiency and raising costs: water quality. Read more…

By Oliver Peckham

Paper Offers ‘Proof’ of Quantum Advantage on Some Problems

October 18, 2018

Is quantum computing worth all the effort being poured into it or should we just wait for classical computing to catch up? An IBM blog today posed those questio Read more…

By John Russell

Dell EMC to Supply U Michigan’s Great Lakes Cluster

October 16, 2018

The University of Michigan (U-M) today announced Dell EMC is the lead vendor for U-M’s $4.8 million Great Lakes HPC cluster scheduled for deployment in first Read more…

By John Russell

Houston to Field Massive, ‘Geophysically Configured’ Cloud Supercomputer

October 11, 2018

Based on some news stories out today, one might get the impression that the next system to crack number one on the Top500 would be an industrial oil and gas mon Read more…

By Tiffany Trader

Nvidia Platform Pushes GPUs into Machine Learning, High Performance Data Analytics

October 10, 2018

GPU leader Nvidia, generally associated with deep learning, autonomous vehicles and other higher-end enterprise and scientific workloads (and gaming, of course) Read more…

By Doug Black

Federal Investment in Exascale – What It Really Means

October 10, 2018

Earlier this month, the EuroHPC JU (Joint Undertaking) reached critical mass, and it seems all EU and affiliated member states, bar the UK (unsurprisingly), have or will sign on. The EuroHPC JU was born from a recognition that individual EU member states, and the EU as a whole, were significantly underinvesting in HPC compared to the US, China and Japan, who all have their own exascale investment and delivery strategies (NSCI, 13th 5 Year Plan, Post-K, etc). Read more…

By Dairsie Latimer

NERSC-9 Clues Found in NERSC 2017 Annual Report

October 8, 2018

If you’re eager to find out who’ll supply NERSC’s next-gen supercomputer, codenamed NERSC-9, here’s a project update to tide you over until the winning bid and system details are revealed. The upcoming system is referenced several times in the recently published 2017 NERSC annual report. Read more…

By Tiffany Trader

TACC Wins Next NSF-funded Major Supercomputer

July 30, 2018

The Texas Advanced Computing Center (TACC) has won the next NSF-funded big supercomputer beating out rivals including the National Center for Supercomputing Ap Read more…

By John Russell

IBM at Hot Chips: What’s Next for Power

August 23, 2018

With processor, memory and networking technologies all racing to fill in for an ailing Moore’s law, the era of the heterogeneous datacenter is well underway, Read more…

By Tiffany Trader

Requiem for a Phi: Knights Landing Discontinued

July 25, 2018

On Monday, Intel made public its end of life strategy for the Knights Landing "KNL" Phi product set. The announcement makes official what has already been wide Read more…

By Tiffany Trader

CERN Project Sees Orders-of-Magnitude Speedup with AI Approach

August 14, 2018

An award-winning effort at CERN has demonstrated potential to significantly change how the physics based modeling and simulation communities view machine learni Read more…

By Rob Farber

House Passes $1.275B National Quantum Initiative

September 17, 2018

Last Thursday the U.S. House of Representatives passed the National Quantum Initiative Act (NQIA) intended to accelerate quantum computing research and developm 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

New Deep Learning Algorithm Solves Rubik’s Cube

July 25, 2018

Solving (and attempting to solve) Rubik’s Cube has delighted millions of puzzle lovers since 1974 when the cube was invented by Hungarian sculptor and archite Read more…

By John Russell

D-Wave Breaks New Ground in Quantum Simulation

July 16, 2018

Last Friday D-Wave scientists and colleagues published work in Science which they say represents the first fulfillment of Richard Feynman’s 1982 notion that Read more…

By John Russell

Leading Solution Providers

HPC on Wall Street 2018 Booth Video Tours Playlist

Arista

Dell EMC

IBM

Intel

RStor

VMWare

TACC’s ‘Frontera’ Supercomputer Expands Horizon for Extreme-Scale Science

August 29, 2018

The National Science Foundation and the Texas Advanced Computing Center announced today that a new system, called Frontera, will overtake Stampede 2 as the fast Read more…

By Tiffany Trader

HPE No. 1, IBM Surges, in ‘Bucking Bronco’ High Performance Server Market

September 27, 2018

Riding healthy U.S. and global economies, strong demand for AI-capable hardware and other tailwind trends, the high performance computing server market jumped 28 percent in the second quarter 2018 to $3.7 billion, up from $2.9 billion for the same period last year, according to industry analyst firm Hyperion Research. Read more…

By Doug Black

Intel Announces Cooper Lake, Advances AI Strategy

August 9, 2018

Intel's chief datacenter exec Navin Shenoy kicked off the company's Data-Centric Innovation Summit Wednesday, the day-long program devoted to Intel's datacenter Read more…

By Tiffany Trader

GPUs Power Five of World’s Top Seven Supercomputers

June 25, 2018

The top 10 echelon of the newly minted Top500 list boasts three powerful new systems with one common engine: the Nvidia Volta V100 general-purpose graphics proc Read more…

By Tiffany Trader

Germany Celebrates Launch of Two Fastest Supercomputers

September 26, 2018

The new high-performance computer SuperMUC-NG at the Leibniz Supercomputing Center (LRZ) in Garching is the fastest computer in Germany and one of the fastest i Read more…

By Tiffany Trader

MLPerf – Will New Machine Learning Benchmark Help Propel AI Forward?

May 2, 2018

Let the AI benchmarking wars begin. Today, a diverse group from academia and industry – Google, Baidu, Intel, AMD, Harvard, and Stanford among them – releas Read more…

By John Russell

Aerodynamic Simulation Reveals Best Position in a Peloton of Cyclists

July 5, 2018

Eindhoven University of Technology (TU/e) and KU Leuven research group conducts the largest numerical simulation ever done in the sport industry and cycling discipline. The goal was to understand the aerodynamic interactions in the peloton, i.e., the main pack of cyclists in a race. Read more…

Houston to Field Massive, ‘Geophysically Configured’ Cloud Supercomputer

October 11, 2018

Based on some news stories out today, one might get the impression that the next system to crack number one on the Top500 would be an industrial oil and gas mon Read more…

By Tiffany Trader

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