title: In vitro measurement of drug efficiency index to aid early lead optimization.
abstract: The concepts of drug efficiency (D(eff) ) and Drug Efficiency Index (DEI) have been recently introduced as useful parameters to optimize the absorption, distribution, metabolism, elimination/excretion, and toxicity properties and in vivo efficacy potential of molecules during lead optimization and at pre-clinical stages. The available free drug concentration relative to dose depends on the compound's bioavailability, clearance, and the nonspecific binding to proteins and phospholipids. In this paper, we have demonstrated, using the data of over 115 known drug molecules, that the nonspecific binding can be determined in vitro very efficiently using biomimetic high-performance liquid chromatography measurements. DEI can therefore be estimated from in vitro measurements. The data show that high in vitro DEI values can be associated with lower efficacious dose. A strategy is described of how to use the DEI parameter during early lead optimization. An example is given to highlight the advantages of optimizing on DEI value rather than on potency alone. In order to facilitate the in silico compound design, correlation between in vitro DEI and in silico ligand efficiency parameters such as ligand lipophilicity efficiency has been revealed, suggesting the potential use of these efficiency-related parameters across lead optimization.
authors.affiliation: Analytical Chemistry, Platform Technology and Science, GlaxoSmithKline, Stevenage, UK. Klara.L.Valko@gsk.com
authors.forename: Klara
authors.initials: K
authors.lastname: Valko
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Chiarparin
authors.forename: Shenaz
authors.initials: S
authors.lastname: Nunhuck
authors.forename: Dino
authors.initials: D
authors.lastname: Montanari
mesh_terms: D000042:Absorption; D001682:Biological Availability; D032701:Biomimetics; D002851:Chromatography, High Pressure Liquid; D055808:Drug Discovery; D066298:In Vitro Techniques; D010599:Pharmacokinetics