Determining success or failure in cholesterol-controlling drugs

May 15, 2009

Researchers at the University of California, San Diego have discovered that a complex network of interactions between drugs and the proteins with which they bind can explain adverse drug effects. Their findings suggest that adverse drug effects might be minimized by using single or multiple drug therapies in order to fine-tune multiple off-target interactions.

"The traditional way of thinking of one drug binding to only one receptor to treat a single disease is outmoded," said Philip Bourne, professor of pharmacology with UC San Diego's Skaggs School of Pharmacy and Pharmaceutical Sciences. "We found that a drug may have a cumulative effect through acting on multiple receptors at the same time, rather than acting on a single receptor."

The term polypharmacology has been coined to describe this phenomenon, which may explain the failure of an anti-cholesterol drug called Torcetrapib which - after 15 years of research and $850 million in development costs - was withdrawn from stage III clinical trials as a result of instances of cardiovascular disease which resulted in death.

"Torcetrapib actually acted on a dozen different receptors, resulting in an unanticipated side effect," said Bourne. "This multi-inhibitor binding pattern may not be at all unusual."

In studying protein-drug interaction networks of a class of drugs known as cholesteryl ester transfer protein (CETP) inhibitors, and aided by computational modeling done at the San Diego Supercomputer Center (SDSC) at UC San Diego, the research team found evidence that CETP inhibitors bind to a variety of receptors. Their work, published in the May 15 issue of PLoS , uses a novel computational strategy to identify protein-ligand binding profiles on a genome-wide scale. In this case, the strategy was applied to explain the molecular mechanisms associated with adverse drug effects.

"At this time we do not have a complete structural proteome to analyze, one that maps all the protein structures in the genome - either experimental or model - to which drugs could bind," said Bourne, director of structural bioinformatics and an SDSC Distinguished Scientist. "So though we still may not have a complete understanding of off-target binding, this strategy is already useful."

Studying the panel of off-targets for Torcetrapib and other CETP inhibitors from the human structural genome, the researchers mapped those targets to biological pathways using the existing literature. "The predicted protein-ligand network is consistent with experimental results from multiple sources and reveals that the side-effects of CETP inhibitors are modulated through the combinatorial control of multiple, interconnected biochemical pathways," said Li Xie, lead author on the study.

In other words, Xie explained, a combination of many different pathways, impacted when a molecule or ligand binds to several receptors, possibly inhibiting a number of different proteins - all lead to the overall physiological effect of that drug.

Besides the CETP inhibitor, Torcetrapib, two related drugs, Anacetrapib and JTT-705, were also analyzed. The final panel of off-targets for these drugs is associated with many physiological processes including cell proliferation, inflammation and hypertension.

"Ironically, Torcetrapib is more specific than JTT705, yet it is less effective in controlling cholesterol levels with minimal side effects," said Lei Xie, a senior scientist in the Bourne group and the major developer of the computational methodology. "This is contrary to conventional wisdom, which implies that the more specific the binding, the fewer the side-effects."

For example, JTT-705 has a binding profile that impacts numerous biological pathways, but none of them result in hypertension - a side effect that is observed in the Torcetrapib, which binds more specifically.

Among a number of cumulative effects, the scientists predicted different binding profiles of CETP inhibitors to several nuclear receptors. They discovered that JTT-705, unlike Torcetrapib, is involved in the activation of nuclear receptors that contribute to both positive and negative control of aldosterone, a hormone responsible for increased blood pressure. This differs from Torcetrapib, which only increases aldosterone production and therefore has a purely positive, or increased, effect on blood pressure.

Mapping the off-targets to biochemical pathways that are currently known provides new insights with the potential to improve the design of effective and safe pharmaceuticals.

"This work extends the scope of chemogenomics - the study of genomic responses to chemical compounds - and exemplifies the role that systems biology has in the future of drug discovery," Bourne said.

Source: University of California - San Diego (news : web)

Related Stories

Recommended for you

Protein Daple coordinates single-cell and organ-wide directionality in the inner ear

December 11, 2017
Humans inherited the capacity to hear sounds thanks to structures that evolved millions of years ago. Sensory "hair cells" in the inner ear have the amazing ability to convert sound waves into electrical signals and transmit ...

Team identifies DNA element that may cause rare movement disorder

December 11, 2017
A team of Massachusetts General Hospital (MGH) researchers has identified a specific genetic change that may be the cause of a rare but severe neurological disorder called X-linked dystonia parkinsonism (XDP). Occurring only ...

Gene therapy improves immunity in babies with 'bubble boy' disease

December 9, 2017
Early evidence suggests that gene therapy developed at St. Jude Children's Research Hospital will lead to broad protection for infants with the devastating immune disorder X-linked severe combined immunodeficiency disorder. ...

In lab research, scientists slow progression of a fatal form of muscular dystrophy

December 8, 2017
In a paper published in the Nature journal Scientific Reports, Saint Louis University (SLU) researchers report that a new drug reduces fibrosis (scarring) and prevents loss of muscle function in an animal model of Duchenne ...

Double-blind study shows HIV vaccine not effective in viral suppression

December 7, 2017
(Medical Xpress)—A large team of researchers from the U.S. and Canada has conducted a randomized double-blind study of the effectiveness of an HIV vaccine and has found it to be ineffective in suppressing the virus. In ...

Time matters: Does our biological clock keep cancer at bay?

December 7, 2017
Our body has an internal biological or "circadian" clock, which cycles daily and is synchronized with solar time. New research done in mice suggests that it can help suppress cancer. The study, publishing 7 December in the ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.