The medicinal chemistry community has become increasingly aware of the value of tracking calculated physical properties. We hypothesized that the shift to high throughput synthetic practices over the past decade may be another factor that has predisposed molecules to fail by steering discovery efforts toward achiral, aromatic compounds.  We have proposed two simple measures of the complexity of molecules prepared as potential drug candidates. The first is carbon bond saturation as defined by fraction sp3 (Fsp3). The second is simply whether a chiral carbon exists in the molecule.  We demonstrate that both complexity (as measured by Fsp3) and the presence of chiral centers correlate with success as compounds transition from discovery, through clinical testing, to drugs. In an attempt to explain these observations, we further demonstrate that saturation correlates with solubility and melting point, physical properties critical to success in the drug discovery setting.

Escape from Flatland: Increasing saturation as an approach to improving clinical success

243rd National Meeting (2012)

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