Medicinal Chemistry

Proteins take steps to bind larger ligands

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Science  08 May 2015:
Vol. 348, Issue 6235, pp. 645-646
DOI: 10.1126/science.348.6235.645-f

In medicinal chemistry, optimizing the binding of a small molecule to a protein target often involves incremental changes to the small molecule. The design process may involve simulations of how a series of molecules binds to the target, but there is little experimental data to inform this analysis. Merski et al. determined the structures of eight benzene compounds, each differing by a single methyl group, binding to the model protein T4 lysozyme. Instead of gradually changing structure, T4 lysozyme transitions between three conformations with different-sized ligand-binding sites. A search of the protein data bank revealed other examples of discrete changes in response to ligand size. Modeling such discrete conformations may be important in drug design.

Proc. Natl. Acad. Sci. U.S.A. 10.1073/pnas.1500806112 (2015).

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