Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), 2-3-26 Aomi, Koto-ku, Tokyo 135-0064, Japan.
Graduate School of Pharmaceutical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Molecules. 2017 Sep 7;22(9):1492. doi: 10.3390/molecules22091492.
The dynamic property of a ligand in the receptor-bound state is an important metric to characterize the interactions in the ligand-receptor interface, and the development of an experimental strategy to quantify the amplitude of motions in the bound state is of importance to introduce the dynamic aspect into structure-guided drug development (SGDD). Fluorine modifications are frequently introduced at the hit-to-lead optimization stage to enhance the binding potency and other characteristics of a ligand. However, the effects of fluorine modifications are generally difficult to predict, owing to the pleiotropic nature of the interactions. In this study, we report an NMR-based approach to experimentally evaluate the local dynamics of trifluoromethyl (CF₃)-containing ligands in the receptor-bound states. For this purpose, the forbidden coherence transfer (FCT) analysis, which has been used to study the dynamics of methyl moieties in proteins, was extended to the F nuclei of CF₃-containing ligands. By applying this CF₃-FCT analysis to a model interaction system consisting of a ligand, AST-487, and a receptor, p38α, we successfully quantified the amplitude of the CF₃ dynamics in the p38α-bound state. The strategy would bring the CF₃-containing ligands within the scope of dynamic SGDD to improve the affinity and specificity for the drug-target receptors.
配体在受体结合状态下的动态特性是表征配体-受体界面相互作用的重要指标，开发一种定量测定结合状态下运动幅度的实验策略对于将动态特性引入基于结构的药物开发（SGDD）非常重要。在从苗头化合物到先导化合物优化阶段，经常会引入氟修饰来增强配体的结合效力和其他特性。然而，由于相互作用的多效性，氟修饰的效果通常难以预测。在这项研究中，我们报告了一种基于 NMR 的方法，用于实验评估受体结合状态下含三氟甲基（CF₃）的配体的局部动力学。为此，我们将已用于研究蛋白质中甲基部分动力学的禁止相干转移（FCT）分析扩展到含 CF₃ 的配体的 F 核。通过将 CF₃-FCT 分析应用于由配体 AST-487 和受体 p38α 组成的模型相互作用系统，我们成功地量化了 p38α 结合状态下 CF₃ 动力学的幅度。该策略将使含 CF₃ 的配体纳入动态 SGDD 的范围，以提高对药物靶标受体的亲和力和特异性。
