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PubMed · 16888652

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

Robert A Copeland·David L Pompliano·Thomas D Meek
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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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Binding, CompetitiveDrug Delivery SystemsDrug DesignHumansKineticsLigandsMacromolecular SubstancesPharmaceutical PreparationsTechnology, PharmaceuticalJournal ArticleReview

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Robert A Copeland, David L Pompliano, Thomas D Meek. 2006-08-04. Drug-target residence time and its implications for lead optimization.. https://doi.org/10.1038/nrd2082

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