School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, U.K.
Cancer Research Horizons, CRUK Scotland Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, U.K.
J Med Chem. 2024 Jun 27;67(12):10025-10034. doi: 10.1021/acs.jmedchem.4c00204. Epub 2024 Jun 7.
Low-affinity protein-ligand interactions are important for many biological processes, including cell communication, signal transduction, and immune responses. Structural characterization of these complexes is also critical for the development of new drugs through fragment-based drug discovery (FBDD), but it is challenging due to the low affinity of fragments for the binding site. Saturation transfer difference (STD) NMR spectroscopy has revolutionized the study of low-affinity receptor-ligand interactions enabling binding detection and structural characterization. Comparison of relaxation and exchange matrix calculations with H STD NMR experimental data is essential for the validation of 3D structures of protein-ligand complexes. In this work, we present a new approach based on the calculation of a reduced relaxation matrix, in combination with funnel metadynamics MD simulations, that allows a very fast generation of experimentally STD-NMR-validated 3D structures of low-affinity protein-ligand complexes.
低亲和力蛋白配体相互作用对许多生物过程很重要，包括细胞通讯、信号转导和免疫反应。这些复合物的结构特征对于通过基于片段的药物发现（FBDD）开发新药也很关键，但由于片段与结合位点的低亲和力，这具有挑战性。饱和转移差（STD）NMR 光谱学彻底改变了低亲和力受体-配体相互作用的研究，使结合检测和结构特征成为可能。与 H STD NMR 实验数据的弛豫和交换矩阵计算的比较对于验证蛋白质-配体复合物的 3D 结构至关重要。在这项工作中，我们提出了一种新方法，该方法基于计算简化的弛豫矩阵，结合漏斗元动力学 MD 模拟，可非常快速地生成经实验 STD-NMR 验证的低亲和力蛋白-配体复合物的 3D 结构。
