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Drug-target residence time and its implications for lead optimization.

Robert A Copeland1, David L Pompliano, Thomas D Meek

  • 1Department of Enzymology and Mechanistic Pharmacology, at GlaxoSmithKline, UP1345, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA. Robert.A.Copeland@gsk.com

Nature Reviews. Drug Discovery
|August 5, 2006
PubMed
Summary

Drug discovery can be optimized by focusing on how long drugs stay bound to their targets, not just how tightly. Longer residence times may improve drug effectiveness and selectivity.

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Area of Science:

  • Pharmacology
  • Drug Discovery
  • Biochemistry

Background:

  • Current drug discovery emphasizes selective targeting of macromolecules by small-molecule drugs.
  • Drug-target binding is considered crucial for pharmacological activity.
  • In vitro drug-target interactions are typically measured by binding parameters like IC(50) or K(d).

Purpose of the Study:

  • To present an alternative perspective on drug optimization.
  • To highlight the significance of drug-target binary complex residence time.
  • To explore the advantages of long residence time for drug efficacy and selectivity.

Main Methods:

  • Quantification of drug-target interactions using dissociative half-life.
  • Analysis of residence time as a key parameter in drug optimization.

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Main Results:

  • Residence time, measured by dissociative half-life, offers a valuable metric for drug optimization.
  • Long residence times can potentially enhance the duration of pharmacological effects.
  • Increased residence times may lead to improved target selectivity.

Conclusions:

  • Drug optimization strategies should consider residence time alongside traditional binding parameters.
  • Focusing on residence time may lead to more effective and selective drugs.
  • This approach offers a novel perspective for advancing drug discovery and development.