Practical application of ligand efficiency metrics in lead optimisation. Issue 11 (15th July 2018)

• Record Type: Journal Article
• Authors: Scott, James S.; Waring, Michael J.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 11(2018)
• Page Start: 3006
• Page End: 3015
• Publication Date: 2018-07-15
• Subjects: Lead optimisation -- Lipophilicity -- Lipophilic ligand efficiency -- Ligand efficiency; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.04.004
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The use of composite metrics that normalise biological potency values in relation to markers of physicochemical properties, such as size or lipophilicity, has gained a significant amount of traction with many medicinal chemists in recent years. However, there is no consensus on best practice in the area and their application has attracted some criticism. Here we present our approach to their application in lead optimisation projects, provide an objective discussion of the principles we consider important and illustrate how our use of lipophilic ligand efficiency enabled the progression of a number of our successful drug discovery projects. We derive, from this and some recent literature highlights, a set of heuristic guidelines for lipophilicity based optimisation that we believe are generally applicable across chemical series and protein targets.