New Compound Approach Could Speed Drug Discovery

Researchers at the Francis Crick Institute and the University of Manchester have created a new way of screening compounds that is more sensitive than existing methods, opening up the possibility of speeding drug discovery new drugs for many diseases.

In the latest study the team developed a new way to screen for 'allosteric' compounds, which regulate the activity of enzymes, by causing enzymes to bind to their substrates either more or less efficiently, or by slowing down or speeding up the rate of the reaction. Compounds that increase efficiency are known as allosteric activators, while those that reduce it are known as allosteric inhibitors.

When several allosteric compounds are present, they can either compete so that one has a dominant effect on enzyme activity or complement each other to create a larger effect. Traditional screening methods mix an individual compound with an enzyme and its substrates, so would not reveal effects that involve more than one allosteric compound. The new method, called CoSPI (compound screening in the presence of an inhibitor), involves screening enzymes and their substrates in the presence of a known allosteric inhibitor to see if any of the test compounds interacts with the inhibitor.

"Allosteric enzymes have important functions in all living things from bacteria to humans, and now we have an improved way of finding new drugs that could work by targeting them," says Luiz Carvalho, Group leader at the Francis Crick Institute.

To show the potential of CoSPI, the team took an enzyme present in tuberculosis (TB) bacteria that speeds up the first step in histidine synthesis- an amino acid essential for humans - and tested compounds on it in the presence of its substrates and a known allosteric inhibitor. They discovered an allosteric compound that successfully competes with the inhibitor, drastically increasing enzyme activity. Ultimately, compounds like this allosteric activator stop proper regulation of metabolic pathways, draining energy from bacteria until they die. Because humans don't have this enzyme - we get histidine from our diet - it is possible that these compounds could be used to kill TB bacteria without harming human cells, making it a possible new drug for TB and other types of bacterial infection.

Their findings are published in Nature Communications.