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The role of ligand efficiency metrics in drug discovery

  • Nature Reviews Drug Discovery volume 13, pages 105121 (2014)
  • doi:10.1038/nrd4163
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Abstract

The judicious application of ligand or binding efficiency metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimized ligand efficiency values for their targets. Optimizing ligand efficiency metrics based on both molecular mass and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the inflation of these properties that has been observed in current medicinal chemistry practice, and to increase the quality of drug candidates.

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Acknowledgements

The authors thank N. Richmond (GlaxoSmithKline) for discussions on the derivation of efficiency metrics; G. Williams (Astex) for fruitful discussion on binding thermodynamics; R. Young (GlaxoSmithKline) for discussions on aromaticity and drug efficiency metrics; and AstraZeneca for providing access to the GVK BIO database.

Author information

Affiliations

  1. Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

    • Andrew L. Hopkins
  2. Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Magyar Tudósok körútja 2., 1525 Budapest, PO Box 17, Hungary.

    • György M. Keserü
  3. GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.

    • Paul D. Leeson
  4. Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK.

    • David C. Rees
  5. Gfree Bio, 3805 Old Easton Road, Doylestown, Pennsylvania 18902, USA.

    • Charles H. Reynolds

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Paul D. Leeson.

Supplementary information

PDF files

  1. 1.

    Supplementary information S1 (figure)

    Ligand efficiencies versus corresponding physical properties.

  2. 2.

    Supplementary information S2 (figure)

    Enthalpy and entropy ligand efficiencies versus properties.

  3. 3.

    Supplementary information S3 (table)

    Mean, median and standard deviations of potencies, LE, LLE and LELP values for collections of oral drugs, Phase II compounds, hits and leads

Excel files

  1. 1.

    Supplementary information S4 (table)

Glossary

Spline fit

A statistical, numerical method for fitting a curve through a set of data points using a cubic polynomial.

p(Activity)

The negative logarithm of activity in vitro in published papers: for example, half-maximal inhibitory concentration (IC50), inhibition constant (Ki) or effector concentration for half-maximum response (EC50) values.