Estimating protein-ligand binding affinity using high-throughput screening by NMR.
Estimating protein-ligand binding affinity using high-throughput screening by NMR.
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DOI：
10.1021/cc800122m
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发表时间：
2008-11
影响因子：
--
通讯作者：
Powers, Robert
中科院分区：
文献类型：
--
作者：
Shortridge, Matthew D.;Hage, David S.;Harbison, Gerard S.;Powers, Robert
今天的许多药物发现项目利用高通量筛选方法，依靠对蛋白质活性的快速评估来对潜在的化学先导物进行排名。通过监测生物学上相关的蛋白质-配体相互作用，核磁共振可以提供一种方法来验证这些发现线索并优化药物发现过程。基于核磁共振的筛选通常使用化学位移或线宽的变化来检测蛋白质与配体的相互作用。然而，目前的核磁共振筛选相对较低的通量和对样品的高要求通常使得收集完整的结合曲线来测量大型多样化学文库中每种化合物的亲和力是不切实际的。因此，核磁共振配体筛选通常仅限于识别与蛋白质结合的候选物，而不给出任何结合亲和力的估计。为了解决这个问题，已经开发了一种方法，基于使用1D 1H核磁共振谱增宽实验的基于核磁共振的屏幕对配体的结合亲和力进行排序。用该方法对12种配体与人血清白蛋白（HSA）的解离平衡常数进行了验证。结果发现，给予良好的协议与先前的亲和力，已报道的这些相同的配体与HSA。
Many of today’s drug discovery programs utilize high-throughput screening methods that rely on quick evaluations of protein activity to rank potential chemical leads. By monitoring biologically relevant protein-ligand interactions, NMR can provide a means to validate these discovery leads and to optimize the drug discovery process. NMR-based screens typically use a change in chemical shift or linewidth to detect a protein-ligand interaction. However, the relatively low throughput of current NMR screens and their high demand on sample requirements generally makes it impractical to collect complete binding curves to measure the affinity for each compound in a large and diverse chemical library. As a result, NMR ligand screens are typically limited to identifying candidates that bind to a protein and do not give any estimate of the binding affinity. To address this issue, a methodology has been developed to rank binding affinities for ligands based on NMR-based screens that use 1D 1H NMR line-broadening experiments. This method was demonstrated by using it to estimate the dissociation equilibrium constants for twelve ligands with the protein human serum albumin (HSA). The results were found to give good agreement with previous affinities that have been reported for these same ligands with HSA.
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影响因子：
2.7
作者：
Bernadó, P;de la Torre, JG;Pons, M
通讯作者：
Pons, M
影响因子：
2.2
作者：
de la Torre, JG;Huertas, ML;Carrasco, B
通讯作者：
Carrasco, B
影响因子：
--
作者：
Fejzo, J;Lepre, CA;Moore, JM
通讯作者：
Moore, JM
影响因子：
--
作者：
Hajduk, PJ;Betz, SF;Fesik, SW
通讯作者：
Fesik, SW
DOI：
10.1016/j.bbrc.2005.06.127
发表时间：
2005-08-26
影响因子：
3.1
作者：
Ascenzi, P;Bocedi, A;Fasano, M
通讯作者：
Fasano, M