Corporate Banner
Satellite Banner
Medicinal Chemistry
Scientific Community
Become a Member | Sign in
Home>News>This Article

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

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 2,600+ scientific posters on ePosters
  • More than 3,800+ 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 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
Atriva Therapeutics GmbH Develops Innovative Flu Drug
Highly effective against seasonal and pandemic influenza.
Study Removes Cancer Doubt for Multiple Sclerosis Drug
Researchers from Queen Mary University of London are calling on the medical community to reconsider developing a known drug to treat people with relapsing Multiple sclerosis after new evidence shows it does not increase the risk of cancer as previously thought.
New Hope for Personalized Treatment of Eczema
Pharmaceutical researchers at Oregon State University have developed a new approach to treat eczema and other inflammatory skin disorders that would use individual tests and advanced science to create personalized treatments based on each person's lipid deficiencies.
Inroads Against Leukaemia
Potential for halting disease in molecule isolated from sea sponges.
Researchers Disguise Drugs As Platelets to Target Cancer
Researchers have for the first time developed a technique that coats anticancer drugs in membranes made from a patient’s own platelets.
HIV Patients Should Be Included in Early Clinical Trials of Anti-TB Drugs
Tuberculosis is the number one cause of death in HIV-infected patients in Africa and a leading cause of death in this population worldwide.
Combination Drug Therapy Shrinks Pancreatic Tumors In Mice
Two drugs that affect the structure and function of DNA have been found to block the growth of pancreatic tumor cells in mice, researchers hope the drugs can soon be tested in humans with the disease.
Seeking A Better Way To Design Drugs
NIH funds research at Worcester Polytechnic Institute to advance a new chemical process for more effective drug development and manufacturing.
Old Drug Performs New Tricks
Cambridge-led research reveals the powers of a "wonder drug" that has lain under the noses of doctors for 50 years.
Diabetes Drugs May Actually Release Sugar Into the Blood
A family of drugs used to treat Type 2 diabetes could promote the release of sugars into the blood - something the drugs are supposed to prevent, Cambridge scientists have claimed.
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
2,600+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,800+ scientific videos