Journal of Computer-Aided Molecular Design

, Volume 25, Issue 7, pp 663–667 | Cite as

Assessing the lipophilicity of fragments and early hits

  • Paul N. MortensonEmail author
  • Christopher W. Murray


A key challenge in many drug discovery programs is to accurately assess the potential value of screening hits. This is particularly true in fragment-based drug design (FBDD), where the hits often bind relatively weakly, but are correspondingly small. Ligand efficiency (LE) considers both the potency and the size of the molecule, and enables us to estimate whether or not an initial hit is likely to be optimisable to a potent, druglike lead. While size is a key property that needs to be controlled in a small molecule drug, there are a number of additional properties that should also be considered. Lipophilicity is amongst the most important of these additional properties, and here we present a new efficiency index (LLEAT) that combines lipophilicity, size and potency. The index is intuitively defined, and has been designed to have the same target value and dynamic range as LE, making it easily interpretable by medicinal chemists. Monitoring both LE and LLEAT should help both in the selection of more promising fragment hits, and controlling molecular weight and lipophilicity during optimisation.


Ligand efficiency Lipophilicity Ligand lipophilicity efficiency Fragment-based drug design Fragment optimisation 



It is a pleasure to acknowledge helpful discussions with colleagues from the medicinal chemistry and computational chemistry groups at Astex, in particular David Rees, Marcel Verdonk and Gianni Chessari.


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Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  1. 1.Astex TherapeuticsCambridgeEngland, UK

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