University of Notre Dame, Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, Notre Dame, Indiana 46556, USA.
J Am Chem Soc. 2010 Apr 28;132(16):5607-9. doi: 10.1021/ja9096779.
Drug design involves iterative ligand modifications. For flexible ligands, these modifications often entail restricting conformational flexibility. However, defining optimal restriction strategies can be challenging if the relationship between ligand flexibility and biological activity is unclear. Here, we describe an approach for ligand flexibility-activity studies using Nuclear Magnetic Resonance (NMR) spin relaxation. Specifically, we use (13)C relaxation dispersion measurements to compare site-specific changes in ligand flexibility for a series of related ligands that bind a common macromolecular receptor. The flexibility changes reflect conformational reorganization resulting from formation of the receptor-ligand complex. We demonstrate this approach on three structurally similar but flexibly differentiated ligands of human Pin1, a peptidyl-prolyl isomerase. The approach is able to map the ligand dynamics relevant for activity and expose changes in those dynamics caused by conformational locking. Thus, NMR flexibility-activity studies can provide information to guide strategic ligand rigidification. As such, they help establish an experimental basis for developing flexibility-activity relationships (FAR) to complement traditional structure-activity relationships (SAR) in molecular design.
药物设计涉及迭代配体修饰。对于柔性配体，这些修饰通常需要限制构象灵活性。然而，如果配体灵活性与生物活性之间的关系不清楚，那么定义最佳的限制策略可能具有挑战性。在这里，我们描述了一种使用核磁共振（NMR）自旋弛豫研究配体灵活性-活性的方法。具体来说，我们使用 (13)C 弛豫色散测量来比较一系列结合共同大分子受体的相关配体的配体特定部位的灵活性变化。这些灵活性变化反映了形成受体-配体复合物导致的构象重排。我们在三种结构相似但灵活性不同的人源 Pin1（一种肽基脯氨酰顺反异构酶）的配体上验证了这种方法。该方法能够映射与活性相关的配体动力学，并揭示构象锁定引起的动力学变化。因此，NMR 灵活性-活性研究可以提供指导策略性配体刚性化的信息。因此，它们有助于建立灵活性-活性关系（FAR）的实验基础，以补充分子设计中的传统结构-活性关系（SAR）。
