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Related Experiment Videos

Drug target residence time: a misleading concept.

Rutger H A Folmer1

  • 1Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 431 83, Sweden.

Drug Discovery Today
|August 8, 2017
PubMed
Summary

Drug target residence time is often overemphasized in drug discovery. Research suggests plain potency, not slow binding kinetics, better predicts drug development success by considering pharmacokinetic context.

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Area of Science:

  • Pharmacology and Drug Discovery
  • Medicinal Chemistry
  • Biophysics

Background:

  • Drug target residence time has gained significant attention in pharmaceutical research over the past decade.
  • Existing literature often presents the residence time concept with potentially misleading simulations and arguments.
  • Compounds are frequently analyzed outside their relevant pharmacokinetic (PK) context.

Purpose of the Study:

  • To critically evaluate the prevailing emphasis on drug target residence time in drug discovery.
  • To investigate the actual advantages and disadvantages of long residence times, particularly concerning pharmacodynamics (PD) and PK.
  • To propose alternative metrics for predicting drug development success.

Main Methods:

  • Review and critique of existing simulations and arguments supporting long residence times.
  • Analysis of drug binding kinetics, focusing on association (on-rate) and dissociation (off-rate).
  • Comparison of residence time with plain potency as predictors of drug development outcomes, considering PK/PD relationships.

Main Results:

  • The concept of residence time is often supported by flawed simulations and arguments.
  • Fast drug association (on-rate) is generally more desirable than slow association.
  • Potential benefits of long residence time, such as PK/PD decoupling, can be negated by slow on-rates.

Conclusions:

  • The current focus on long drug target residence time may be misplaced.
  • Plain potency, reflecting overall drug efficacy and target engagement, is a more reliable predictor of drug development success.
  • Future drug discovery efforts should prioritize potency and consider the full pharmacokinetic context over solely focusing on residence time.

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