The concept of drug-target residence time proposed by Copeland and colleagues has been gaining steady adoption in drug discovery over the last decade. Drug-target residence time is defined as the reciprocal of the first order offset rate of drug dissociating from its target, equivalent to the time needed for approximately 63% dissociation. More generally, the onset and offset rates, respectively, of drug engaging and disengaging a biological target constitute the essential parameters of binding kinetics (BK). BK is now recognized as the key partner with pharmacokinetics (PK) in effectuating pharmacodynamics (PD). A moderate to high throughput measurement of BK parameters is now available to drug discovery scientists. This talk aims at outlining several key experimental methods that can measure BK spanning nine orders of timescale altogether, from milliseconds to days. Pros and cons and practical guidance will be summarized for these experimental approaches such as stopped/quenched flow, various biosensor and label-free technologies, global progress curve analysis, and jump dilution.

Measuring drug-target residence time and binding kinetics: Why and how?

254th National Meeting (2017)

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