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Improvement of Ligand Affinity and Thermodynamic Properties by NMR‐Based Evaluation of Local Dynamics and Surface Complementarity in the Receptor‐Bound State
Author(s) -
Mizukoshi Yumiko,
Takeuchi Koh,
Arutaki Misa,
Tokunaga Yuji,
Takizawa Takeshi,
Hanzawa Hiroyuki,
Shimada Ichio
Publication year - 2016
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201607474
Subject(s) - van der waals force , chemistry , docking (animal) , complementarity (molecular biology) , hydrogen bond , bound state , ligand (biochemistry) , chemical physics , crystallography , stereochemistry , receptor , molecule , physics , quantum mechanics , organic chemistry , biochemistry , biology , genetics , medicine , nursing
The thermodynamic properties of a ligand in the bound state affect its binding specificity. Strict binding specificity can be achieved by introducing multiple spatially defined interactions, such as hydrogen bonds and van der Waals interactions, into the ligand–receptor interface. These introduced interactions are characterized by restricted local dynamics and improved surface complementarity in the bound state. In this study, we experimentally evaluated the local dynamics and the surface complementarity of weak‐affinity ligands in the receptor‐bound state by forbidden coherence transfer analysis in free‐bound exchange systems (Ex‐FCT), using the interaction between a ligand, a myocyte‐enhancer factor 2A (MEF2A) docking peptide, and a receptor, p38α, as a model system. The Ex‐FCT analyses successfully provided information for the rational design of a ligand with higher affinity and preferable thermodynamic properties for p38α.