Abstract
Many cyclic peptide natural products are larger and structurally more complex than conventional small molecule drugs. Although some molecules in this class are known to possess favorable pharmacokinetic properties, there have been few reports on the membrane permeabilities of cyclic peptide natural products. Here, we present the passive membrane permeabilities of 39 cyclic peptide natural products, and interpret the results using a computational permeability prediction algorithm based on their known or calculated 3D conformations. We found that the permeabilities of these compounds, measured in a parallel artificial membrane permeability assay, spanned a wide range and demonstrated the important influence of conformation on membrane permeability. These results will aid in the development of these compounds as a viable drug paradigm.
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Acknowledgements
The authors thank Tadeusz Molinski (UCSD) and Yongsheng Che (Beijing Institute of Pharmacology and Toxicology) for the generous donation of samples for this study.
Financial & competing interests disclosure
KW Lexa (GM100619) and P Crews (R01 CA047135) would like to thank the NIH for funding. MP Jacobson is a consultant to Schrodinger LLC, which distributes some of the software used in this study, and is a founder of Circle Pharma, a macrocycle drug discovery company. RS Lokey is also a cofounder of Circle Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.