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

作者：Frank Lovering, Jack Andrew Bikker, Christine C. Humblet · 发表于：Journal of Medicinal Chemistry · 年份：2009 · DOI：10.1021/jm901241e · 被引用次数：4585 · 研究领域：Computational Drug Discovery Methods、Chemical Synthesis and Analysis、Molecular spectroscopy and chirality

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 sp(3) (Fsp(3)) where Fsp(3) = (number of sp(3) 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 Fsp(3)) 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.