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Nat Rev Drug Discov. 2006 Sep;5(9):730-9. Epub 2006 Aug 4.

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

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

Erratum in

  • Nat Rev Drug Discov. 2007 Mar;6(3):249.

Abstract

Much of drug discovery today is predicated on the concept of selective targeting of particular bioactive macromolecules by low-molecular-mass drugs. The binding of drugs to their macromolecular targets is therefore seen as paramount for pharmacological activity. In vitro assessment of drug-target interactions is classically quantified in terms of binding parameters such as IC(50) or K(d). This article presents an alternative perspective on drug optimization in terms of drug-target binary complex residence time, as quantified by the dissociative half-life of the drug-target binary complex. We describe the potential advantages of long residence time in terms of duration of pharmacological effect and target selectivity.

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