Researchers at the University of California, San Diego (UCSD) have come up with a computer based technique that allows the identification of potentialside effects of medicines before they are tested in humans.
The new technique has been used to study a class of drugs that includes
tamoxifen, the most prescribed drug in the treatment of breast cancer.
research attains significance because early identification of adverse
effects is crucial in developing new therapeutics, and also because
unexpected effects account for a third of all drug failures during the
online report posted at PLoS Computational Biology says that the new
technique helps screen specific drug molecules using a worldwide
repository, the Protein Data Bank (PDB), containing tens of thousands
of three-dimensional protein structures.
molecules of medicines achieve therapeutic affects by attaching to
targeted proteins. But if a small drug molecule attaches to an
off-target protein that has a similar binding site or "lock", side
effects can result.
identifying which proteins may be unintended targets, the researchers
take a single drug molecule and look for how it may bind to as many of
the proteins encoded by the human proteome as possible.
a case study, the researchers looked at Select Estrogen Receptor
Modulators (SERMs), a class of drug that includes tamoxifen, to
illustrate the novel approach.
computer procedure we developed starts with an existing
three-dimensional model of a pharmaceutical, showing the structure of a
drug molecule bound to its target protein; in this case, the SERM bound
to the estrogen receptor," said Dr. Philip Bourne, Professor of
Pharmacology at UCSD's Skaggs School of Pharmacy and Pharmaceutical
research team then used computer analysis to search for other binding
sites that matched that drug-binding site. This work led to the
discovery of a previously unidentified protein target for SERMs.
identification of this secondary binding site explains known adverse
effects, and opens the door to modifying the drug in a way that
maintains binding to the intended target, but reduces binding to the
a drug has adverse side effects, it is likely that drug is also binding
to an unintended, secondary molecule; in other words, the key that
allows it to attach to its target fits more than one lock," said Bourne.
revealed that using the new computational technique to find another
"lock" could result in one of the three thingsthe new lock might show
no effect, the lock could explain an adverse side effect of the drug,
or the research could potentially discover a new therapeutic effect for
an existing drug.
said that the research team was continuing its studies, which could be
applied to any medicine on the market for which a structure of the drug
bound to the receptor exists in the PDB.
He, however, admitted that the results from the new approach still needed to be tested experimentally.