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March 2, 2018updated 31 Oct 2021 2:12pm

Universal enzyme inhibition measurement could boost drug discovery

Researchers at McGill University in Montreal, Canada have developed a new method for measuring enzyme inhibition, offering a new way to discern the efficacy of previously overlooked drug candidates.

Researchers at McGill University in Montreal, Canada have developed a new method for measuring enzyme inhibition, offering a new way to discern the efficacy of previously overlooked drug candidates.

The study, led by chemistry professors Nicolas Moitessier and Anthony Mittermaier, with findings published in Nature Communications, was based on the link between a treatment’s efficacy and the kinetics of its interaction with a molecular target.

The researchers used isothermal titration calorimetry (ITC) to measure the kinetics of enzyme activity, more specifically monitoring heat generated and the rates at which inhibitors blocked the activity. Many medications work by blocking the action of enzymes, from antibiotics to chemotherapy drugs, and finding new enzyme-inhibiting substances remains a key focus for drug developers.

Currently only indirect methods for measuring enzyme activity exist, monitoring changes in concentration caused by enzymatic catalysis as a function of time. Existing measurements often use special reagents that change in colour or fluorescence when exposed to the enzyme. These reagents usually require individual tests to be developed for each enzyme studied. By comparison, ITC measures heat production, which is a near-universal by-product of chemical reactions, meaning the method can be applied to almost every enzyme.

“One key difference between ITC and other methods is that ITC measures the rate of reaction directly,” Mittermaier said. “ITC is as close as you can get to a universal enzyme test.”

Another benefit of ITC is that it measures heat production in real time, providing direct insight into the process of enzyme inhibition as it occurs, information that is difficult to obtain when using conventional methods. This is of particular use to those examining covalent inhibitors, with ITC allowing a view into an inhibitor’s molecular structure and how it relates to its target. Covalent inhibitors have the potential as long-acting drugs, but previous efforts have been abandoned due to toxicity concerns. However, the ITC method offers hope that these strong-binding molecules can form the basis of effective and safe new treatments.

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“While there is growing evidence that long residence times lead to more effective therapeutics, drug development is still geared much more towards optimising affinities rather than kinetics,”  Mittermaier told Drug Development Technology. “Our hypothesis is that kinetic information is currently under-utilised in the drug development process. Our technique helps to address this problem, since it is a relatively straightforward procedure for measuring inhibition kinetics that can be robustly applied to just about any enzyme system. We anticipate that the immediate impact of the work will be to facilitate kinetics-based decision making.

“It will make it easier to pick leads with favourable kinetic properties and to assess the effects of chemical modifications on those kinetic properties. We believe that will help to more efficiently reach molecules that are ready for clinical testing.”

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