Interrogating cyclic peptide natural products from an ADME perspective: Beyond cyclosporine A.

In terms of chemical diversity and complexity, the database of known natural products easily trumps the average diversity screening collection. Indeed, most small molecule screening libraries are pre-filtered using classical metrics for drug likeness (e.g., Lipinski's Rule of 5) that necessarily limit the size and complexity of their constituents. These metrics would categorize most natural products as non-druglike, despite numerous clinically prescribed examples to the contrary. Many of these “beyond-Rule of 5” (b-Ro5) success stories include macrocyclic peptides like cyclosporine A (CSA), which has a molecular weight of 1200 and is both cell permeable and orally bioavailable. While CSA has been the poster child representing this new b-Ro5 modality, there are many other natural product cyclic peptides that have structural motifs (e.g., backbone N-methylation, mostly hydrophobic side chains, the presence of D-amino acids) that also suggest the potential for passive permeability. However, the rich chemical landscape of macrocyclic peptides has not been explored from a chemo-informatics perspective, and so we set out to analyze all known cyclic peptide natural products using various quantitative metrics relevant to ADME and pharmacokinetics. To do this we extracted structural information from a comprehensive database of natural products and filtered it for cyclic peptide like species. I will present a survey of the resulting compounds with a focus in particular on structure/property relationships relevant to cell permeability and oral bioavailability.