Novel screening method gives pharma shot in the arm
24 Aug 2017 by Evoluted New Media
Scientists at the Francis Crick Institute have created a new, more responsive method to screen potential drugs.
Scientists at the Francis Crick Institute have created a new, more responsive method to screen potential drugs.
Working alongside researchers from the University of Manchester, this new technique screens allosteric compounds which regulate enzyme activity by altering their catalytic capability. It is hoped it will hasten drug development as well as finding new uses for existing drugs and compounds in pharmaceutical libraries.
Dr Luiz Carvalho, group leader at the Francis Crick Institute, said: “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.”
Allosteric compounds affect enzymes by causing them to bind to their substrates more or less efficiently, influencing the rate of reaction. When several allosteric compounds are present, they either complement each other or compete to have a dominant effect on enzyme activity.
Traditional screening methods combine a single compound with an enzyme and its substrates, so cannot reveal effects that involve more than one allosteric compound. The researchers’ new technique, compound screening in the presences of an inhibitor (CoSPI), screens enzymes and their substrates with a known allosteric inhibitor to observe any enzyme interaction.
The researchers tested an enzyme present in Mycobacterium tuberculosis that accelerates the first step in histidine synthesis – an essential human amino acid. The enzyme was tested with a number of different compounds in the presence of substrates and a known allosteric inhibitor. The scientists found an allosteric compound that successfully competed with the inhibitor and swiftly increased enzyme activity.
Similar compounds prevent proper regulation of metabolic pathways, draining energy from bacteria until they die. As humans cannot synthesise histidine, it is possible that these compounds could be used to kill Mycobacterium tuberculosis bacteria without harming human cells. This could lead a new drug to treat tuberculosis and other bacterial infections.
Dr Cesira de Chiara, a researcher at the Crick Institute, said: “Our method allows us to find out early on how compounds interact to change enzyme activity. We can find out more information in fewer experiments, which helps accelerate the drug discovery process." The paper was published in Nature Communications.
