The presence of an unpaired electron in paramagnetic molecules generates significant effects in NMR spectra, which can be exploited to provide restraints complementary to those used in standard structure-calculation protocols. NMR already occupies a central position in drug discovery for its use in fragment screening, structural biology and validation of ligand–target interactions. Paramagnetic restraints provide unique opportunities, for example, for more sensitive screening to identify weaker-binding fragments. A key application of paramagnetic NMR in drug discovery, however, is to provide new structural restraints in cases where crystallography proves intractable. This is particularly important at early stages in drug-discovery programs where crystal structures of weakly-binding fragments are difficult to obtain and crystallization artefacts are probable, but structural information about ligand poses is crucial to guide medicinal chemistry. Numerous applications show the value of paramagnetic restraints to filter computational docking poses and to generate interaction models. Paramagnetic relaxation enhancements (PREs) generate a distance-dependent effect, while pseudo-contact shift (PCS) restraints provide both distance and angular information. Here, we review strategies for introducing paramagnetic centers and discuss examples that illustrate the utility of paramagnetic restraints in drug discovery. Combined with standard approaches, such as chemical shift perturbation and NOE-derived distance information, paramagnetic NMR promises a valuable source of information for many challenging drug-discovery programs.

顺磁性分子中不成对电子的存在会对 NMR 谱产生显着影响，可利用其提供与标准结构计算方案中使用的限制互补的限制。 NMR 因其在片段筛选、结构生物学和配体-靶标相互作用验证中的应用而在药物发现中占据了中心地位。顺磁性约束提供了独特的机会，例如，可以进行更灵敏的筛选以识别较弱的结合片段。然而，顺磁核磁共振在药物发现中的一个关键应用是在晶体学难以解决的情况下提供新的结构限制。这在药物发现项目的早期阶段尤其重要，因为弱结合片段的晶体结构很难获得，并且很可能出现结晶假象，但有关配体位姿的结构信息对于指导药物化学至关重要。许多应用显示了顺磁约束在过滤计算对接姿势和生成交互模型方面的价值。顺磁弛豫增强 (PRE) 会产生距离相关的效应，而伪接触位移 (PCS) 约束则提供距离和角度信息。在这里，我们回顾了引入顺磁中心的策略，并讨论了说明顺磁约束在药物发现中的效用的示例。顺磁 NMR 与化学位移扰动和 NOE 衍生距离信息等标准方法相结合，为许多具有挑战性的药物发现项目提供了宝贵的信息来源。