Computer Technology To Detect Drug Side Effects

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.

This 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 development process.

An 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.

The 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.

For 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.

During a case study, the researchers looked at Select Estrogen Receptor Modulators (SERMs), a class of drug that includes tamoxifen, to illustrate the novel approach.

“The 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 Sciences.

The 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.

The 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 second site.

“If 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.

He revealed that using the new computational technique to find another “lock” could result in one of the three things—the 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.

Bourne 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.

Source-ANI
KAR/P