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Medicinal chemistry

Exploring the third dimension

Nature Reviews Drug Discovery volume 8, page 931 (2009)Cite this article

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The authors chose two measures to reflect molecular complexity: the extent of bond saturation and the number of chiral centres. The rationale behind this choice was that increased levels of saturation — defined by the fraction of sp3 hybridized carbons (Fsp3) — makes the compound more three-dimensional in shape and an increased number of chiral centres increases the number of potential isomers of the compound. Such effects on molecular shape might allow for improved interactions with the target protein, enhancing the potency and/or specificity of the drug candidate and increasing the probability that it will lead to a successful drug. Importantly, these effects are achieved without substantially increasing molecular mass — a key consideration for drug-likeness noted in the Rule of 5.

Using these measures, the authors analysed the GVK BIO database of compounds in various stages of drug development. They found that Fsp3 increased by 31% from discovery, to Phase I–III clinical trials and eventually to drug status. A comparable increase over the course of development was seen for chiral centres, even when molecules that violated any one of the Rule of 5 parameters were excluded from the analysis. Finally, saturation was shown to correlate with solubility, a physical property that is known to be important for success in drug discovery.

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References

ORIGINAL RESEARCH PAPER

  1. Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009)

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FURTHER READING

  1. Leeson, P. D. & Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nature Rev. Drug Discov. 6, 881–890 (2007)

    Article  CAS  Google Scholar 

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Authors
  1. Katie Kingwell
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Kingwell, K. Exploring the third dimension. Nat Rev Drug Discov 8, 931 (2009). https://doi.org/10.1038/nrd3058

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