Macrocycles are of interest for drug discovery, particularly for protein-protein systems where relatively large and featureless surfaces are thought to necessitate larger ligands to achieve drug-like binding affinity.  Macrocyclization may offer an avenue to improved pharmaceutical properties for such larger small-molecule drugs.  Despite having diverse chemical structures, “macrocycles” are often considered as a single chemotype.  A recent survey lists 68 marketed macrocycle drugs and 35 macrocyclic compounds in clinical development, and these molecules show diversity in both chemical structure and discovery provenance.  Most arose from natural product-based drug discovery efforts, but a few are purely synthetic.  We are interested in the structure-based design of purely synthetic small-molecule macrocycles, an area of drug discovery that has not been heavily  explored.  We present simple metrics that facilitate the detection and prioritization of bound ligands that may be particularly suited to macrocyclization.  Representative examples of such macrocyclic-like compounds from both the Cambridge Structural Database (CSD) and Protein Data Bank (PDB) will be presented for discussion.<br/>

Simple metrics to identify opportunities for macrocyclization of small-molecule ligands<i> </i>

256th National Meeting (2018)

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