Corporate Banner
Satellite Banner
ADME Tox
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Computer Model Successfully Predicts Drug Side Effects

Published: Tuesday, June 12, 2012
Last Updated: Tuesday, June 12, 2012
Bookmark and Share
Research based on the similarity between a drugs chemical structures and those molecules known to cause side effects, according to a paper appearing online this week in the journal Nature.

The team, co-led by researchers in the UCSF School of Pharmacy, Novartis Institutes for BioMedical Research (NIBR) and SeaChange Pharmaceuticals, Inc. — a UCSF spinoff company launched by two of the paper’s authors — set out to test how well a computer model could help researchers eliminate risky drug prospects by identifying which ones were most likely to have adverse side effects.

Drugs frequently interact with more than one target, with hundreds of these targets linked to the side effects of clinically used therapeutics. Focusing on 656 drugs that are currently prescribed, with known safety records or side effects, the team was able to predict such undesirable targets — and thus potential side effects — half of the time.

That’s a significant leap forward from previous work, which has never tackled hundreds of compounds at once, according to Brian Shoichet, Ph.D., a UCSF professor of pharmaceutical chemistry who was the joint advisor on the project alongside Laszlo Urban, M.D., Ph.D., at Novartis.

As a result, it offers a possible new way for researchers to focus their efforts on developing the compounds that will be safest for patients, while potentially saving billions of dollars each year that goes into studying and developing drugs that fail.

“The biggest surprise was just how promiscuous the drugs were, with each drug hitting more than 10 percent of the targets, and how often the side-effect targets were unrelated to the previously known targets of the drugs,” said Shoichet, whose lab is renowned for its work in using computational simulations to identify new targets for known drugs. “That would have been hard to predict using standard scientific approaches.”

Adverse drug effects are the second most common reason, behind effectiveness, that potential drugs fail in clinical trials, according to the paper. The cost of developing an approvable drug is frequently cited at about $1 billion across 15 years, although recent estimates have ranged as high as $4 billion to $12 billion per drug, depending upon how many of these failures are included in the estimate.

“This basically gives you a computerized safety panel, so someday, when you’re deciding among hundreds of thousands of compounds to pursue, you could run a computer program to prioritize for those that may be safest,” said Michael Keiser, Ph.D., co-first author of the paper, who started working on the project as a doctoral student in Shoichet’s lab and co-founded SeaChange with Shoichet and John Irwin, Ph.D., also of UCSF, upon graduation.

It also offers the possibility for identifying possible new uses for medications that are already on the market, according to Peter Preusch, Ph.D., who oversees structure-based drug design grants at the National Institutes of Health’s National Institute of General Medical Sciences, which partly supported the study.

“By providing a way to identify the unintended targets of a drug, this advance will not only help streamline the drug development pipeline, but also will provide valuable guidance in efforts to repurpose existing drugs for new diseases and conditions,” Preusch said. “This work represents a notable contribution that is likely to find broad applications in the pharmaceutical arena.”

The project builds on UCSF’s legacy as a leader in developing computer-based approaches to efficiently screen millions of chemicals for those with the best potential for drug development. The UCSF School of Pharmacy was the first to develop computer-based molecular “docking” software, which both public and private researchers use to visualize how potential drugs might attach to target molecules to inhibit their function. It also builds upon UCSF’s commitment to industry collaborations that advance pharmaceutical science. Novartis has one of the strongest and most productive drug pipelines in the industry, with more than 130 projects in clinical development, according to the company.

The current project is based on technology UCSF developed, known as the “similarity ensemble approach” (SEA), which compares the shape of each drug to thousands of other compounds and uses that to predict which proteins they might both bind to — essentially, guilt by association. The technique was named among Wired magazine’s “Top Scientific Breakthroughs of 2009.”

In this project, the UCSF and SeaChange team ran a computer screen on 656 drugs that are currently in clinical use to predict which ones were most likely to bind to the 73 target proteins that appear on Novartis’ safety panel for testing drugs for side effects such as heart attacks.  Meanwhile, NIBR developed a statistical method of relating those targets to known side effects.

The computer model identified 1,241 possible side-effect targets for the 656 drugs, of which 348 were confirmed by Novartis’ proprietary database of drug interactions. Another 151 hits revealed potential side effects that had never been identified for these drugs, yet which Novartis confirmed through lab testing. Among those was a synthetic form of estrogen that has been known for years to cause stomach pain, with no known cause. The screen showed that it binds strongly to a target known as COX-1, which is the protein target of non-steroidal anti-inflammatory drugs, such as aspirin, which also can cause stomach pain, ulceration, and bleeding.

Keiser is co-first author on the Nature paper alongside Eugen Lounkine, Ph.D., a postdoctoral scholar in the Novartis Institutes for Biomedical Research whose postdoctoral advisors are Urban and Shoichet.

Additional authors include Steven Whitebread, Dmitri Mikhailov and Jeremy Jenkins, from the NIBR’s facilities in Cambridge, Mass.; Jacques Hamon, Eckhard Weber and Serge Côté, from NIBR in Basel, Switzerland; and Allison Doak, in the UCSF Department of Pharmaceutical Chemistry.

The project was supported by the National Institutes of Health and by the QB3 Rogers Family Foundation Bridging-the-Gap Award. The authors declare competing financial interests in the project: both Shoichet and Keiser are co-founders of SeaChange, which is developing the method to find new therapeutic uses of known drugs and address toxicology issues. Details are available in the online version of the article at www.nature.com/nature.


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,000+ scientific posters on ePosters
  • More than 4,400+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Crowdfunding the Fight Against Cancer
From budding social causes to groundbreaking businesses to the next big band, crowdfunding has helped connect countless worthy projects with like-minded people willing to support their efforts, even in small ways. But could crowdfunding help fight cancer?
Monday, February 08, 2016
Embryonic Switch for Cancer Stem Cell Generation
An international team of scientists report that decreases in a specific group of proteins trigger changes in the cancer microenvironment that accelerate growth and development of therapy-resistant cancer stem cells (CSCs).
Wednesday, December 02, 2015
Some 3-D Printed Objects Are Toxic
Researchers at the University of California, Riverside have found parts produced by some commercial 3-D printers are toxic to certain fish embryos.
Monday, November 09, 2015
Double Enzyme Hit May Explain Common Cancer Drug Side Effect
Mouse study suggests genomic screening before treatment may help prevent anemia.
Wednesday, October 14, 2015
Designing New Pain Relief Drugs
Researchers have identified the molecular interactions that allow capsaicin to activate the body’s primary receptor for sensing heat and pain, paving the way for the design of more selective and effective drugs to relieve pain.
Thursday, June 11, 2015
Powerful Anti-Cancer Compound Safely Delivered
Researchers have discovered a way to effectively deliver staurosporine (STS).
Tuesday, October 22, 2013
Mouse Models Point to Potential Therapy for Alzheimer's
Scientists demonstrate a new potential target in the fight against Alzheimer's and other neurodegenerative diseases.
Thursday, June 27, 2013
Blocking Inflammation can Prevent Heart Attack Damage
New research from UC Davis shows that blocking an enzyme that promotes inflammation can prevent the tissue damage following a heart attack that often leads to heart failure.
Tuesday, March 26, 2013
FDA, UCSF Partnership Helps Industry Identify Drug Interactions
Goal is to find risks before drugs reach patients.
Wednesday, September 05, 2012
UCLA Researcher Developing Lab to Help Manufacturer Testing
UCLA team has developed a testing method to assess the safety and health risks of engineered nanomaterials.
Wednesday, February 08, 2006
Scientific News
Cell Transplant Treats Parkinson’s in Mice
A University of Wisconsin—Madison neuroscientist has inserted a genetic switch into nerve cells so a patient can alter their activity by taking designer drugs that would not affect any other cell.
Understanding Female HIV Transmission
Glowing virus maps points of entry through entire female reproductive tract for first time.
Experimental Drug Cancels Effect from Key Intellectual Disability Gene
A University of Wisconsin—Madison researcher who studies the most common genetic intellectual disability has used an experimental drug to reverse — in mice — damage from the mutation that causes the syndrome.
Common Class of Cancer Drugs May Not Lead to Cognitive Decline
UCLA study refutes 2015 research suggesting anthracyclines could cause memory loss, other impairments.
Designing Better Drugs
A rational drug engineering approach could breathe new life into drug development.
Genetic Approach May Lead to New Treatments for Digestive Diseases
Researchers at UMass Medical School have identified a new molecular pathway critical for maintaining the smooth muscle tone that allows the passage of materials through the digestive system.
Potential Target for Revolutionary Antibiotics
An international team of including the Lomonosov Moscow State University researchers discovered which enzyme enables Escherichia coli bacterium (E. coli) to breathe.
Unique Model for Studying ALS
Unique mouse model will allow researchers to better study the genetic origins and potential treatments of ALS.
Factors Influencing Influenza Vaccine Effectiveness Uncovered
The long-held approach to predicting seasonal influenza vaccine effectiveness may need to be revisited, new research suggests.
New Model to Enhance Zika Virus Research
The model will allow researchers to better understand how the virus causes disease and aid in the development of antiviral compounds and vaccines.
SELECTBIO

SELECTBIO Market Reports
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,000+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,400+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!