Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 54, Issue 11, Pages 3290-3327Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201408487
Keywords
dipolar interactions; molecular recognition; protein-ligand complexation; supramolecular chemistry; water
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Funding
- ETH research council
- F. Hoffmann-La Roche, Basel
- Chugai
- Genentech
- German Fonds der Chemischen Industrie
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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 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.
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