Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, New Jersey 07065, United States.
J Med Chem. 2014 Jan 23;57(2):477-94. doi: 10.1021/jm401600u. Epub 2014 Jan 2.
Systematic methods that speed-up the assignment of absolute configuration using vibrational circular dichrosim (VCD) and simplify its usage will advance this technique into a robust platform technology. Applying VCD to pharmaceutically relevant compounds has been handled in an ad hoc fashion, relying on fragment analysis and technical shortcuts to reduce the computational time required. We leverage a large computational infrastructure to provide adequate conformational exploration which enables an accurate assignment of absolute configuration. We describe a systematic approach for rapid calculation of VCD/IR spectra and comparison with corresponding measured spectra and apply this approach to assign the correct stereochemistry of nine test cases. We suggest moving away from the fragment approach when making VCD assignments. In addition to enabling faster and more reliable VCD assignments of absolute configuration, the ability to rapidly explore conformational space and sample conformations of complex molecules will have applicability in other areas of drug discovery.
系统方法可以加速使用振动圆二色性（VCD）进行绝对构型的分配，并简化其使用，从而将该技术推进为强大的平台技术。将 VCD 应用于药物相关化合物的处理一直是一种特别的方式，依赖于碎片分析和技术捷径来减少所需的计算时间。我们利用大型计算基础设施提供充分的构象探索，从而能够准确地分配绝对构型。我们描述了一种快速计算 VCD/IR 光谱的系统方法，并将其与相应的实测光谱进行比较，并将该方法应用于分配九个测试案例的正确立体化学。我们建议在进行 VCD 分配时避免使用碎片方法。除了能够更快、更可靠地进行绝对构型的 VCD 分配外，快速探索构象空间和采样复杂分子构象的能力在药物发现的其他领域也具有适用性。
