title: Drug-target residence time and its implications for lead optimization.
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.
authors.affiliation: Department of Enzymology and Mechanistic Pharmacology, at GlaxoSmithKline, UP1345, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA. Robert.A.Copeland@gsk.com
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.forename: David L
authors.initials: DL
authors.lastname: Pompliano
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Meek
mesh_terms: D001667:Binding, Competitive; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008024:Ligands; D046911:Macromolecular Substances / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D008024:Ligands; D046911:Macromolecular Substances; D004364:Pharmaceutical Preparations