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. 2014 May 9;5(6):616-8.
doi: 10.1021/ml500146d. eCollection 2014 Jun 12.

Validity of ligand efficiency metrics

Christopher W Murray  1 , Daniel A Erlanson  2 , Andrew L Hopkins  3 , György M Keserü  4 , Paul D Leeson  5 , David C Rees  1 , Charles H Reynolds  6 , Nicola J Richmond  5
Affiliations

Validity of ligand efficiency metrics

Christopher W Murray et al. ACS Med Chem Lett. .

Abstract

A recent viewpoint article (Improving the plausibility of success with inefficient metrics. ACS Med. Chem. Lett. 2014, 5, 2-5) argued that the standard definition of ligand efficiency (LE) is mathematically invalid. In this viewpoint, we address this criticism and show categorically that the definition of LE is mathematically valid. LE and other metrics such as lipophilic ligand efficiency (LLE) can be useful during the multiparameter optimization challenge faced by medicinal chemists.

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Figures

Figure 1
Figure 1
Tankyrase inhibitors where the same single atom addition (i.e, ring expansion) has been performed on molecules 1 and 3 that are of different sizes. Structures and data (including LE and LLE/LipE values) are taken from ref (5). IC50 is given in μM and LE is given in (kcal/mol)/heavy atom.
Figure 2
Figure 2
Effect on overall fuel efficiency (FE) of adding the same inefficient stage of 100 miles in town traffic to two fuel efficient journeys of different length.
See this image and copyright information in PMC

References

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    1. The units arise directly from the conversion of an equilibrium constant (often approximated by the IC50) into a free energy of binding using one of the fundamental laws of chemistry (ΔG = −RT ln K).