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Practical application of ligand efficiency metrics in lead optimisation

Lookup NU author(s): Professor Mike Waring



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


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.

Publication metadata

Author(s): Scott JS, Waring MJ

Publication type: Article

Publication status: Published

Journal: Bioorganic & Medicinal Chemistry

Year: 2018

Volume: 26

Issue: 11

Pages: 3006-3015

Print publication date: 15/07/2018

Online publication date: 05/04/2018

Acceptance date: 02/04/2018

Date deposited: 09/04/2018

ISSN (print): 0968-0896

ISSN (electronic): 1464-3391

Publisher: Pergamon Press


DOI: 10.1016/j.bmc.2018.04.004


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