Rapid measurement of inhibitor binding kinetics by isothermal titration calorimetry

Justin M. Di Trani, Stephane De Cesco, Rebecca O’Leary, Jessica Plescia, Claudia Jorge Nascimento, Nicolas Moitessier and Anthony K. Mittermaier ()
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Justin M. Di Trani: McGill University
Stephane De Cesco: McGill University
Rebecca O’Leary: McGill University
Jessica Plescia: McGill University
Claudia Jorge Nascimento: McGill University
Nicolas Moitessier: McGill University
Anthony K. Mittermaier: McGill University

Nature Communications, 2018, vol. 9, issue 1, 1-7

Abstract: Abstract Although drug development typically focuses on binding thermodynamics, recent studies suggest that kinetic properties can strongly impact a drug candidate’s efficacy. Robust techniques for measuring inhibitor association and dissociation rates are therefore essential. To address this need, we have developed a pair of complementary isothermal titration calorimetry (ITC) techniques for measuring the kinetics of enzyme inhibition. The advantages of ITC over standard techniques include speed, generality, and versatility; ITC also measures the rate of catalysis directly, making it ideal for quantifying rapid, inhibitor-dependent changes in enzyme activity. We used our methods to study the reversible covalent and non-covalent inhibitors of prolyl oligopeptidase (POP). We extracted kinetics spanning three orders of magnitude, including those too rapid for standard methods, and measured sub-nM binding affinities below the typical ITC limit. These results shed light on the inhibition of POP and demonstrate the general utility of ITC-based enzyme inhibition kinetic measurements.

Date: 2018
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DOI: 10.1038/s41467-018-03263-3

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