Canvass: A Crowd-Sourced, Natural Product Screening Library for Exploring Biological Space

Abstract

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(<i>S</i>)-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.

Therapeutic candidates for the Zika virus identified by a high-throughput screen for Zika protease inhibitors

“…The pilot screen was performed using the Microsource Discovery Spectrum collection, http://www.msdiscovery.com/spectrum.html. All other screening compounds were from the NCATS/NIH (46,47), https:// ncats.nih.gov/preclinical/core/compound. Additional compounds and substrates were obtained from Sigma, Abcam, Cayman Chemicals, Genscript, Bachem, or Cambridge Research Biochemicals.…”

Drug design targeting active posttranslational modification protein isoforms

“…There are two factors contributing to the small biologically relevant chemical space, one is small overlap of biological space and chemical space, and the other is that some parts of biological space have not been populated by the chemical biology probes 21 . A natural product‐oriented compound library, Canvass, has been developed to explore the biological space 37 . Recently, a new international project, Target 2035, 38 was initiated aiming at developing chemogenomic libraries, chemical probes, and/or functional antibodies for the entire proteome, which will expand the biological space.…”