Flexible binding pocket

One remarkable aspect of the EC structure is that, although both EpoA and PTX ligands occupy the same binding cavity, each one interacts with the amino acid side chains of the binding site in an unrelated and unique way. This fact rules out the hypothesis of a common pharmacophore for Epo and PTX. It may turn out to be a property of rather flexible binding pockets to accommodate different small molecules in detail differently. 

Automatic flexible docking of molecules into the binding pocket, e.g., in order to study structure-activity/selectivity relationships... 

Muscimol and 4-PIOL are assumed to bind to the same binding site, but a direct superimposition of the amino groups and the 3-isoxazolol rings, which make up the pharmacophore elements in these compounds, seems impossible. However, owing to the flexibility of the arginine, this side chain can adopt an extended as well as a bent conformation, which makes it feasible to accommodate muscimol and 4-PIOL in the same binding pocket as illustrated in Fig. 6A. 

A., Gustafsson, J.A. and Carlquist, M. (2003) The three-dimensional structure of the liver X receptor beta reveals a flexible ligand-binding pocket that can accommodate fundamentally different ligands. The Journal of Biological Chemistry, 278, 38821-38828. 

We have shown that the conformational behavior of natural aminoglycosides is characterized by a remarkable flexibility, with different conformations, even non-exo-anomeric ones, in fast exchange. This feature allows the adaptation of these ligands to the spatial and electronic requirements of the different receptors. The large diversity of structures adopted by aminoglycosides in the binding pocket of the different RNA receptors and the enzymes involved in bacterial resistance is consistent with this view. 

Nilmeier, J., Jacobson, M. Multiscale Monte Carlo sampling of protein sidechains application to binding pocket flexibility. J. Chem. Theory Comput. 2008, 4, 835-46. 

Molecular dynamics (MD) should be performed for binding pockets defined mostly by side chains of flexible protein residues to generate an ensemble of binding sites. Such an ensemble can be used for subsequent docking or virtual screening in a parallel fashion. 

In trypsinogen, a region of the protein at the binding pocket is disordered, indicating conformational flexibility.133,134 On activation or on the addition of a small peptide that can bind to the buried Asp-194, this region takes on a well-defined structure. 

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