![]() ![]() We have designed scaffolding reagents that are easily integrated into peptide structure to afford diverse ring connectivities and embedded heterocyclic motifs ( 15 – 20). Our laboratory seeks to identify structural settings in which macrocycles can retain ancillary polar groups yet achieve a useful balance of cell permeability and aqueous solubility ( Fig. Molecular shape and conformational dynamics have also been cited as important factors for achieving this end ( 2, 12 – 14). Empirical analysis of data suggests macrocycles having molecular weight (MW) < 1,000 Da, total polar surface area (TPSA) < 250 Å 2, clogP < 10, and fewer than five hydrogen bond donors are more likely to be bioavailable. Nevertheless, some general trends have emerged. In the forty years since the discovery of cyclosporine as a membrane-permeable and orally bioavailable drug, efforts to anticipate related structures with comparable properties have had limited success ( 12). The advent of several high-throughput biosynthetic platforms has transformed macrocyclic peptides into a powerful ligand discovery modality ( 6 – 10). Peptide-derived macrocycles are especially attractive for targeting protein surfaces because the embedded peptide can mimic native protein structure and recognition elements ( 4, 5). The ring structures of macrocycles contribute to structural preorganization, lowering entropic penalties for binding to biological targets ( 1 – 3). Macrocyclic compounds have been identified as enzyme inhibitors, as GPCR (G protein-coupled receptor) agonists and antagonists, inhibitors of protein–protein interactions, and as modulators of various other biological pathways. ![]() ![]() Our approach deeply probes ligand space accessible via our synthetic methodology and provides a resource for large-scale virtual screening. For conformational analyses, we also introduce ConfBuster++, an RDKit port of the open-source software ConfBuster, which allows facile integration with CPMG and ready parallelization for better scalability. Structures are generated based on predicted site reactivity and filtered on the basis of physical and three-dimensional properties to identify maximally diverse compounds for prioritization. Our open-source platform, CPMG (Composite Peptide Macrocycle Generator), has algorithmically generated a library of 2,020,794,198 macrocycles that can result from the multistep reaction sequences we have developed. We now describe a computational rendering of our methodology that creates an in silico three-dimensional library of composite peptidic macrocycles. The hypothetical scope of the methodology is vast and far outpaces the capacity of our experimental format. These methods create macrocycles and embed condensed heterocycles to diversify outcomes and improve pharmacological properties. Our laboratory has developed robust methods that integrate small-peptide units into designed scaffolds. Structures of this type having precise shapes and drug-like character are particularly coveted, but are relatively difficult to synthesize. ![]() Peptidomimetic macrocycles have the potential to regulate challenging therapeutic targets. ![]()
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