Ligand Proton Pseudocontact Shifts Determined from Paramagnetic Relaxation Dispersion in the Limit of NMR Intermediate Exchange
Ligand Proton Pseudocontact Shifts Determined from Paramagnetic Relaxation Dispersion in the Limit of NMR Intermediate Exchange
复制标题
核磁共振中间交换极限下顺磁弛豫色散确定的配体质子赝接触位移
DOI：
10.1021/acs.jpclett.8b01443
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发表时间：
2018
影响因子：
5.7
通讯作者：
Ruan K
中科院分区：
文献类型：
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作者：
Xu Difei;Li Bin;Gao Jia;Nshogoza Gilbert;Zhang Jiahai;Wu Jihui;He Wei;Liu Zhijun;Niu Xiaogang;Su Xun-Cheng;Yang Daiwen;Ma RS;Yang DW;Ruan K
蛋白质-配体相互作用模式的描述是合理药物发现的关键。复杂晶体结构的可用性通常受到化合物的水溶性的限制，而具有微摩尔亲和力的类铅化合物通常落入NMR中间体交换体系，其中严重的谱线展宽到超出界面共振的检测限制了NMR应用。在这里，我们开发了一种新的方法来检索低人口的束缚态1H赝接触位移（PCS）使用顺磁弛豫色散（RD）。我们在BRM布罗莫结构域铅样抑制剂中使用1H PCS-RD方法进行评估，以使用多个分子间结构限制来过滤分子对接位姿。考虑到质子原子在类药物化合物中的普遍存在，即使在NMR中间体交换和配体低水溶性的极端条件下，我们的工作也将在结构指导的药物发现中具有广泛的应用。
Delineation of protein–ligand interaction modes is key for rational drug discovery. The availability of complex crystal structures is often limited by the aqueous solubility of the compounds, while lead-like compounds with micromolar affinities normally fall into the NMR intermediate exchange regime, in which severe line broadening to beyond the detection of interfacial resonances limits NMR applications. Here, we developed a new method to retrieve low-populated bound-state1H pseudocontact shifts (PCSs) using paramagnetic relaxation dispersion (RD). We evaluated using a1H PCS-RD approach in a BRM bromodomain lead-like inhibitor to filter molecular docking poses using multiple intermolecular structural restraints. Considering the universal presence of proton atoms in druglike compounds, our work will have wide application in structure-guided drug discovery even under an extreme condition of NMR intermediate exchange and low aqueous solubility of ligands.