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 IC₅₀ 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.

Author affiliations

1. Robert A. Copeland is in the Department of Enzymology and Mechanistic Pharmacology, at GlaxoSmithKline, UP1345, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.
2. David L. Pompliano is in MMPD Biology, at GlaxoSmithKline, UP1345, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.
3. Thomas D. Meek is in Assay Development, at GlaxoSmithKline, UP1345, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.

Correspondence to: Robert A. Copeland¹ Email: Robert.A.Copeland@gsk.com

Published online 4 August 2006

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