Ligand Preorganization May Be Accompanied by Entropic Penalties in Protein–Ligand Interactions
Aaron P. Benfield, Martin G. Teresk, Hilary R. Plake, John E. DeLorbe, Laura E. Millspaugh, Stephen F. Martin · Angewandte Chemie International Edition · 2006
Fact or fiction? It is generally assumed that preorganization of a flexible ligand in the 3D shape it adopts when bound to a macromolecular receptor will provide a derivative with an increased binding affinity that benefits entropically (see picture). Contrary to this fundamental tenet of molecular recognition, it is shown that ligand preorganization in biological systems does not necessarily have a favorable entropic component.