Laboratorium für Organische Chemie, Departement Chemie und Angewandte Biowissenschaften, ETH Zürich, Vladimir-Prelog-Weg 3, 8093 Zürich (Switzerland).
Angew Chem Int Ed Engl. 2015 Mar 9;54(11):3290-327. doi: 10.1002/anie.201408487. Epub 2015 Jan 28.
Structure-based ligand design in medicinal chemistry and crop protection relies on the identification and quantification of weak noncovalent interactions and understanding the role of water. Small-molecule and protein structural database searches are important tools to retrieve existing knowledge. Thermodynamic profiling, combined with X-ray structural and computational studies, is the key to elucidate the energetics of the replacement of water by ligands. Biological receptor sites vary greatly in shape, conformational dynamics, and polarity, and require different ligand-design strategies, as shown for various case studies. Interactions between dipoles have become a central theme of molecular recognition. Orthogonal interactions, halogen bonding, and amide⋅⋅⋅π stacking provide new tools for innovative lead optimization. The combination of synthetic models and biological complexation studies is required to gather reliable information on weak noncovalent interactions and the role of water.
基于结构的配体设计在药物化学和作物保护中依赖于识别和量化弱非共价相互作用，并理解水的作用。小分子和蛋白质结构数据库搜索是检索现有知识的重要工具。热力学分析，结合 X 射线结构和计算研究，是阐明配体取代水的能量学的关键。生物受体位点在形状、构象动力学和极性方面差异很大，需要不同的配体设计策略，各种案例研究表明了这一点。偶极子之间的相互作用已成为分子识别的核心主题。正交相互作用、卤键和酰胺⋅⋅⋅π堆积为创新的先导优化提供了新的工具。需要结合合成模型和生物络合研究来收集关于弱非共价相互作用和水的作用的可靠信息。
