Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success
Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success
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DOI：
10.1021/jm901241e
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发表时间：
2009-11-12
影响因子：
7.3
通讯作者：
Humblet, Christine
中科院分区：
文献类型：
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作者：
Lovering, Frank;Bikker, Jack;Humblet, Christine
药物化学界已经越来越意识到跟踪计算的物理性质的价值，如分子量、拓扑极性表面积、可旋转键和氢键供体和受体。我们假设，过去十年向高通量合成实践的转变可能是另一个因素，可能会通过将发现努力转向无手性、芳香族化合物而使分子容易失败。我们已经提出了两个简单和可解释的措施来衡量作为潜在候选药物制备的分子的复杂性。第一种是碳键饱和度，由分数sp(3)(fsp(3))定义，其中fsp(3)=(sp(3)杂化碳数/总碳数)。第二个简单的问题是分子中是否存在手性碳。我们证明，复杂性(由FSP(3)衡量)和手性中心的存在都与其化合物从发现到临床测试到药物的成功过渡相关。为了解释这些观察结果，我们进一步证明了饱和度与溶解度相关，这是一种对药物发现环境中的成功很重要的实验物理性质。
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 its 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.