Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The assay data generated were analyzed using a variety of quality control metrics, and the resultant assay profiles were explored using statistical methods, such as clustering and compound promiscuity analyses. Individual compounds were then sorted by structural class and activity profiles. Differential behavior based on these classifications, as well as noteworthy activities, are outlined herein. One such highlight is the activity of (−)-2(S)-cathafoline, which was found to stabilize calcium levels in the endoplasmic reticulum. The workflow described here illustrates a pilot effort to broadly survey the biological potential of natural products by utilizing the power of automation and high-throughput screening.
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This research was supported by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (NIH). R.B.A. acknowledges support from NSF (CHE-1665145) and NIH (GM126221). M.K.B. acknowledges support from NIH (5R01GM110131). N.Z.B. thanks support from NIGMS, NIH (R01GM114061). J.K.C. acknowledges support from NSF (CHE-1665331).
Due to the large number of funding sources, only the first few are listed in this section. For the complete list of funding sources, please download this article.
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscentsci.8b00747.
Kearney, Sara E.; Zahoránszky-Kőhalmi, Gergely; Brimacombe, Kyle R.; Henderson, Mark J.; Lynch, Caitlin; Zhao, Tongan; Wan, Kanny K.; Itkin, Zina; Dillon, Christopher; Shen, Min; Cheff, Dorian M.; Lee, Tobie D.; Bougie, Danielle; Cheng, Ken; Coussens, Nathan P.; Dorjsuren, Dorjbal; Eastman, Richard T.; Huang, Ruili; Iannotti, Michael J.; Karavadhi, Surendra; Klumpp-Thomas, Carleen; Roth, Jacob S.; Sakamuru, Srilatha; Sun, Wei; Titus, Steven A.; Yasgar, Adam; Zhang, Ya-Qin; Zhao, Jinghua; Andrade, Rodrigo B.; Brown, M. Kevin; and Grossman, Robert B., "Canvass: A Crowd-Sourced, Natural-Product Screening Library for Exploring Biological Space" (2018). Chemistry Faculty Publications. 145.