ACS Chem. Biol., 2017, 12 (10), pp 2644–2651
Abstract: Natural products represent an inexhaustible source of novel
therapeutic agents. Their complex and constrained three-dimensional
structures endow these molecules with exceptional biological properties,
thereby giving them a major role in drug discovery programs. However,
the search for new bioactive metabolites is hampered by the chemical
complexity of the biological matrices in which they are found. The
purification of single constituents from such matrices requires such a
significant amount of work that it should be ideally performed only on
molecules of high potential value (i.e., chemical novelty and biological
activity). Recent bioinformatics approaches based on mass spectrometry
metabolite profiling methods are beginning to address the complex task
of compound identification within complex mixtures. However, in parallel
to these developments, methods providing information on the bioactivity
potential of natural products prior to their isolation are still lacking
and are of key interest to target the isolation of valuable natural
products only. In the present investigation, we propose an integrated
analysis strategy for bioactive natural products prioritization. Our
approach uses massive molecular networks embedding various informational
layers (bioactivity and taxonomical data) to highlight potentially
bioactive scaffolds within the chemical diversity of crude extracts
collections. We exemplify this workflow by targeting the isolation of
predicted active and nonactive metabolites from two botanical sources
(Bocquillonia nervosa and Neoguillauminia cleopatra) against two
biological targets (Wnt signaling pathway and chikungunya virus
replication). Eventually, the detection and isolation processes of a
daphnane diterpene orthoester and four 12-deoxyphorbols inhibiting the
Wnt signaling pathway and exhibiting potent antiviral activities against
the CHIKV virus are detailed. Combined with efficient metabolite
annotation tools, this bioactive natural products prioritization
pipeline proves to be efficient. Implementation of this approach in drug
discovery programs based on natural extract screening should speed up
and rationalize the isolation of bioactive natural products.