Corporate Banner
Satellite Banner
Medicinal Chemistry
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
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 2,500+ scientific posters on ePosters
  • More than 3,700+ 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

Cancer Survival Rates will be Boosted by Drug Development
Bristol-Myers Squib’s research chief discusses pharmaceutical innovations at UCSF cancer center showcase.
Monday, December 10, 2012
Preventing Cells from Getting the Kinks Out of DNA
Discovery could pave the way for new research into how to re-design these drugs to make them more effective poisons for cancer cells and harmful bacteria.
Monday, May 24, 2010
Scientific News
Combining Chemotherapy With Immune-Blocking Drug Could Stop Cancer Growing Back
Giving patients a drug that blocks part of the immune system from going into overdrive might help prevent cancer coming back in some people.
Researchers Pioneer Use of Capsules to Save Materials
Wax capsule delivery systems can simplify a wide range of chemistry transformations.
Photoredox Catalyst Unlocks New Pathways for Nickel Chemistry
Using a light-activated catalyst, researchers have unlocked a new pathway in nickel chemistry to construct carbon-oxygen (C-O) bonds that would be highly valuable to pharmaceutical and agrochemical industries.
Scientists Determine How Antibiotic Gains Cancer-Killing Sulfur Atoms
In a discovery with implications for future drug design scientists have shown an unprecedented mechanism for how a natural antibiotic with antitumor properties incorporates sulfur into its molecular structure, an essential ingredient of its antitumor activity.
Familiar Drugs May Block Ebola Virus Infection
A well-known class of molecules, many of which are already in use therapeutically, may be able to block the Ebola virus’s entry into cells and halt the disease in its tracks, according to researchers at the University of Illinois at Chicago.
New Extra ‘Sticky’ Microgel Could Revolutionise Bladder Cancer Treatment
Researchers have designed a new super-efficient way of delivering an anti-cancer drug which could extend and improve the quality of life for bladder cancer patients - and perhaps save lives.
Common Class of ‘Channel Blocking’ Drugs May Find a Role in Cancer Therapy
Discoveries in fruit flies prompt unusual treatment of patient with metastatic disease.
Common Medications Could Delay Brain Injury Recovery
Drugs used to treat common complaints could delay the recovery of brain injury patients according to research by University of East Anglia (UEA) and University of Aberdeen scientists, published today in Brain Injury.
Scientists Make Strides in Therapy Preventing Addiction Relapse
Single Injection of Drug Candidate Prevents Meth Relapse in Animal Models.
New Clot-Busting Treatments Target Number One Killer
Australian researchers funded by the National Heart Foundation are a step closer to a safer and more effective way to treat heart attack and stroke via nanotechnology.
Skyscraper Banner

Skyscraper Banner
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
2,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!