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Macrocycles In Drug Discovery

December 14, 2009 | A version of this story appeared in Volume 87, Issue 50

I read with interest your article on the use of macrocycles in drug discovery (C&EN, Sept. 7, page 54). I have two comments: First, macrocycles may not exhibit planar chirality at physiological temperatures, but they probably bind in a chiral fashion and perhaps with chiral selectivity (J. Am. Chem. Soc. 2001, 123, 2107; in this case, the compound did exhibit planar chirality). Second, in regard to the relationship between conformation and binding, I commend the review "Binding Affinities of Host-Guest, Protein-Ligand, and Protein-Transition-State Complexes" (Angew. Chem. Int. Ed. 2003, 42, 4872), which, in addition to the works by Martin and Spaller referenced in the article, dispels the "prevailing belief ... that preorganizing a molecule lowers the entropic penalty experienced on binding to a protein." That is, despite the temptation to speculate otherwise, "there is no thermodynamic reason that this relationship [between binding enthalpy and binding entropy] should be linear" or correlated by another functional (Houk et al.). Indeed, in Martin's work the opposite relationship was observed.

Christian S. Hamann
Lancaster, Pa.

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