Journal of Computer-Aided Molecular Design

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

Assessing the lipophilicity of fragments and early hits

Article

Abstract

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.

Keywords

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

References

  1. 1.
    Hopkins AL, Groom CR, Alex A (2004) Drug Discov Today 9:430–431CrossRefGoogle Scholar
  2. 2.
    Kuntz ID, Chen K, Sharp KA, Kollman PA (1999) Proc Natl Acad Sci USA 96:9997–10002CrossRefGoogle Scholar
  3. 3.
    Carr RA, Congreve M, Murray CW, Rees DC (2005) Drug Discov Today 10:987–992CrossRefGoogle Scholar
  4. 4.
    Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Adv Drug Deliv Rev 23:3–25CrossRefGoogle Scholar
  5. 5.
    Reynolds CH, Bembenek SD, Tounge BA (2007) Bioorg Med Chem Lett 17:4258–4261CrossRefGoogle Scholar
  6. 6.
    Reynolds CH, Tounge BA, Bembenek SD (2008) J Med Chem 51:2432–2438CrossRefGoogle Scholar
  7. 7.
    Nissink JW (2009) J Chem Inf Model 49:1617–1622CrossRefGoogle Scholar
  8. 8.
    Abad-Zapatero C, Metz JT (2005) Drug Discov Today 10:464–469CrossRefGoogle Scholar
  9. 9.
    Hajduk PJ (2006) J Med Chem 49:6972–6976CrossRefGoogle Scholar
  10. 10.
    Wenlock MC, Austin RP, Barton P, Davis AM, Leeson PD (2003) J Med Chem 46:1250–1256CrossRefGoogle Scholar
  11. 11.
    Van de Waterbeemd H, Smith DA, Beaumont K, Walker DK (2001) J Med Chem 44:1313–1333CrossRefGoogle Scholar
  12. 12.
    Leeson PD, Springthorpe B (2007) Nat Rev Drug Discov 6:881–890CrossRefGoogle Scholar
  13. 13.
    Ryckmans T, Edwards MP, Horne VA, Correia AM, Owen DR, Thompson LR, Tran I, Tutt MF, Young T (2009) Bioorg Med Chem Lett 19:4406–4409CrossRefGoogle Scholar
  14. 14.
    Keseru GM, Makara GM (2009) Nat RevDrug Discov 8:203–212CrossRefGoogle Scholar
  15. 15.
    Verdonk ML, Rees DC (2008) Chem Med Chem 3:1179–1180Google Scholar
  16. 16.
    Watson P, Verdonk ML, Hartshorn MJ (2003) J Mol Graph Model 22:71–82CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  1. 1.Astex TherapeuticsCambridgeEngland, UK

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