Article ID Journal Published Year Pages File Type
2030537 Trends in Biochemical Sciences 2015 6 Pages PDF
Abstract

•Disordered proteins are highly prevalent in human disease, including cancer, neurodegeneration, cardiovascular conditions and diabetes.•No clinically approved drug directly targets disordered proteins. A better understanding of how small molecules bind disordered proteins may help change this situation.•Enthalpy-based rational drug design, which is a powerful approach for targeting globular proteins, has not yet led to major advances for disordered proteins.•Relatively few cases are known in which entropic contributions are the main driving force of protein–ligand binding. We propose that exploiting systematically these contributions may help target disordered proteins.

The human proteome includes many disordered proteins. Although these proteins are closely linked with a range of human diseases, no clinically approved drug targets them in their monomeric forms. This situation arises, at least in part, from the current lack of understanding of the mechanisms by which small molecules bind proteins that do not fold into well-defined conformations. To explore possible solutions to this problem, we discuss quite generally how an overall decrease in the free energy associated with intermolecular binding can originate from different combinations of enthalpic and entropic contributions. We then consider more specifically a mechanism of binding by which small molecules can affect the conformational space of a disordered protein by creating an entropic expansion in which more conformations of the protein become populated.

Related Topics
Life Sciences Biochemistry, Genetics and Molecular Biology Biochemistry
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