Molecular Recognition in Chemical and Biological Systems

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. T...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2015-03, Vol.54 (11), p.3290-3327
Main Authors: Persch, Elke, Dumele, Oliver, Diederich, François
Format: Article
Language:English
Subjects:
Biological
Biological Science Disciplines
Chemical bonds
Chemistry, Pharmaceutical
Design engineering
dipolar interactions
Ligands
Models, Molecular
molecular recognition
Optimization
protein–ligand complexation
Receptors
Recognition
Searching
supramolecular chemistry
water
Water - chemistry
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Summary: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. Both are required: Chemical model systems and the study of biological receptors are both required to understand molecular recognition processes. The identification and quantification of noncovalent interactions and deciphering the role of water are key elements for structure‐based drug design. Several case studies are presented in which weak intermolecular interactions were applied to innovative ligand design and optimization.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201408487