Gossert Alvar D, Henry Christelle, Blommers Marcel J J, Jahnke Wolfgang, Fernández César
Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002, Basel, Switzerland.
J Biomol NMR. 2009 Apr;43(4):211-7. doi: 10.1007/s10858-009-9303-5. Epub 2009 Feb 11.
The identification of compounds that bind to a protein of interest is of central importance in contemporary drug research. For screening of compound libraries, NMR techniques are widely used, in particular the Water-Ligand Observed via Gradient SpectroscopY (WaterLOGSY) experiment. Here we present an optimized experiment, the polarization optimized WaterLOGSY (PO-WaterLOGSY). Based on a water flip-back strategy in conjunction with model calculations and numerical simulations, the PO-WaterLOGSY is optimized for water polarization recovery. Compared to a standard setup with the conventional WaterLOGSY, time consuming relaxation delays have been considerably shortened and can even be omitted through this approach. Furthermore, the robustness of the pulse sequence in an industrial setup was increased by the use of hard pulse trains for selective water excitation and water suppression. The PO-WaterLOGSY thus yields increased time efficiency by factor of 3-5 when compared with previously published schemes. These time savings have a substantial impact in drug discovery, since significantly larger compound libraries can be tested in screening campaigns.
在当代药物研究中，识别与目标蛋白结合的化合物至关重要。对于化合物库的筛选，核磁共振（NMR）技术被广泛应用，尤其是通过梯度光谱法观察水-配体（WaterLOGSY）实验。在此，我们展示了一种优化实验——极化优化的WaterLOGSY（PO-WaterLOGSY）。基于水反转策略并结合模型计算和数值模拟，PO-WaterLOGSY针对水极化恢复进行了优化。与传统WaterLOGSY的标准设置相比，耗时的弛豫延迟已大幅缩短，甚至通过这种方法可以省略。此外，通过使用硬脉冲序列进行选择性水激发和水抑制，提高了工业设置中脉冲序列的稳健性。因此，与先前发表的方案相比，PO-WaterLOGSY的时间效率提高了3至5倍。这些时间节省在药物发现中具有重大影响，因为在筛选活动中可以测试显著更大的化合物库。
