A class of molecules that has received significant attention in recent years, in part due to their potential utility against low druggability targets, is that of synthetic macrocycles. However, the specific features of protein-macrocycle interactions and what makes them successful, even where traditional drugs fail, have not been well studied. In this work we investigated the ligand characteristics and target interactions of a set comprising primarily natural product macrocycle-protein complexes with structures available in the PDB. We were interested in structural features of the macrocyclic ligands alone as well as any trends in the binding mode with their protein partner. The macrocycle properties identified here will aid in our understanding of the molecule class as a whole, in addition to informing design criteria that can be used in future synthetic schemes.

How proteins bind macrocycles: Lessons for the design of macrocyclic compound libraries for drug discovery

245th National Meeting (2013)

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