Quantifying biogenic bias in screening libraries

Abstract

In lead discovery, libraries of 106 molecules are screened for biological activity. Given the over 1060 drug-like molecules thought possible, such screens might never succeed. The fact that they do, even occasionally, implies a biased selection of library molecules. We have developed a method to quantify the bias in screening libraries toward biogenic molecules. With this approach, we consider what is missing from screening libraries and how they can be optimized.

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Figure 1
Figure 2: Compounds in screening libraries are biased toward biogenic molecules.
Figure 3: Biogenic bias increases with molecular size.
Figure 4: Core ring structures common among drugs and related molecules.

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Acknowledgements

This work was supported by US National Institutes of Health grant GM59957 to B.K.S. J.H. was supported by a Marie Curie fellowship from the 6th Framework Program of the European Commission; M.J.K. was supported by a US National Science Foundation graduate fellowship; C.L. was supported by a fellowship from the Max Kade Foundation.

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Contributions

The project was conceived of by J.H. and B.K.S. J.H. undertook most of the calculations, with molecular proof checking by J.J.I. and C.L. and algorithmic assistance from M.J.K. J.H. and B.K.S. wrote the manuscript, which was read and commented on by the other authors.

Corresponding author

Correspondence to Brian K Shoichet.

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Supplementary Figures 1–4 and Supplementary Tables 1–3 (PDF 306 kb)

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Hert, J., Irwin, J., Laggner, C. et al. Quantifying biogenic bias in screening libraries. Nat Chem Biol 5, 479–483 (2009). https://doi.org/10.1038/nchembio.180

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