Drug target residence time: a misleading concept.

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.