Theoretical future for drug design

Swiss researchers have found a way to search for new and improved versions of common drugs by combining computer simulations with an assay. 

A team led by Erick Carreira at the Swiss Federal Institute of Technology (ETH) in Zurich used computer simulations to design molecules that would closely resemble one of the currently available anti-cholesterol drugs, ezetimibe. The drug reduces the amount of cholesterol in the blood by blocking its absorption in the gut. Unfortunately, at the core of the drug is a β-lactam ring, a highly strained fragment that decomposes in acidic and basic conditions similar to those in the human body.  

Using the computer models, the group was able to suggest alternative rings that would hold the other fragments of the molecule in similar orientations to those in the active drug. The models worked not only in theory, but in practice. Carreira’s team made the ezetimibe analogues and found that one showed a similar activity to the drug.  

The team developed a new assay to allow it to measure rapidly the biological activity of the compounds. The method uses small fragments of small intestine wall, called brush border membrane vesicles, to mimic cholesterol absorption in the human body. The assay avoids costly and time consuming animal tests.  

A future aim of the project is to use the new compounds to study the mechanism of absorption of cholesterol and other lipids which, comments Tobias Ritter, a member of the ETH group, is a ’topic of enormous current interest in human health’.  

Celia Clarke