Drug-target residence time: critical information for lead optimization

Area of Science:

• Pharmacology and Drug Discovery
• Medicinal Chemistry

Background:

• Poor in vivo efficacy is a major cause of new chemotherapeutic failure during development.
• Current lead optimization often focuses solely on drug-target binding affinity, neglecting in vivo pharmacokinetics.

Purpose of the Study:

• To highlight the limitations of optimizing only drug-target binding affinity.
• To advocate for the inclusion of drug-target residence time in drug discovery.

Main Methods:

• Analysis of factors contributing to chemotherapeutic attrition.
• Review of current lead optimization strategies in drug discovery.
• Conceptual framework emphasizing drug-target complex lifetime.

Main Results:

• Optimizing solely for binding affinity is insufficient for predicting in vivo efficacy.
• Drug concentration fluctuations in vivo are critical and often overlooked.
• Drug-target residence time directly influences drug action duration.

Conclusions:

• Incorporating drug-target residence time measurements enhances the correlation between in vitro and in vivo drug activity.
• A revised approach to lead optimization is necessary for successful drug development.
• Focusing on both affinity and residence time will improve therapeutic outcomes.