Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success

TLDR

The medicinal chemistry community increasingly tracks calculated physical properties such as molecular weight, topological polar surface area, rotatable bonds, and hydrogen bond donors and acceptors. The study hypothesizes that the shift toward high‑throughput synthesis over the past decade may steer discovery toward achiral, aromatic compounds that are more likely to fail. The authors propose two simple, interpretable complexity metrics: the fraction of sp3 carbons (Fsp3) and the presence of a chiral center. They find that higher Fsp3 and chiral centers correlate with greater success from discovery to clinical testing to approved drugs, and that saturation also correlates with solubility, an important physical property.

Abstract

The medicinal chemistry community has become increasingly aware of the value of tracking calculated physical properties such as molecular weight, topological polar surface area, rotatable bonds, and hydrogen bond donors and acceptors. We hypothesized that the shift to high-throughput synthetic practices over the past decade may be another factor that may predispose molecules to fail by steering discovery efforts toward achiral, aromatic compounds. We have proposed two simple and interpretable measures of the complexity of molecules prepared as potential drug candidates. The first is carbon bond saturation as defined by fraction sp3 (Fsp3) where Fsp3 = (number of sp3 hybridized carbons/total carbon count). 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, an experimental physical property important to success in the drug discovery setting.