Bioactive Natural Products Prioritization Using Massive Multi-informational Molecular Networks

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.

New Benthic Cyanobacteria from Guadeloupe Mangroves as Producers of Antimicrobials

“…Using the aforementioned criteria, these strains are congeneric, and can be assigned to three new hypothetical species represented by strain PMC 1075. 18…”

“…Even though, no perfect match was generated through DEREPLICATOR algorithm, marine peptide natural products were proposed and therefore support the relevance of this tool for the exploration of peptide diversity. Furthermore, on the basis of the taxonomic annotation, some clusters were restricted to a single genus indicating the chemical uniqueness of the features within the whole map and, potential structural originality ( Figure S1) [18]. Table 1.…”

“…Most of the cyanobacterial strains showed moderate activity against P. atlantica with a mean growth inhibition of 20% to 60%; three Jaaginema strains PM 1078. 18 Figure S1).…”

Innovative omics-based approaches for prioritisation and targeted isolation of natural products – new strategies for drug discovery

“…8 In academic laboratories, the screening of collections of a few hundred extracts corresponding to a dened corpus is typical in focused studies. [9][10][11][12][13][14] These small collections are easier to handle. Their size is compatible with concomitant metabolite proling and mining and with the capacities of tools currently available for NP prioritisation studies as discussed below.…”

“…In this respect, an innovative LC-MS/MS-MN-based approach has been developed for the screening of a focused library of Euphorbiaceae plant species. 10,59,60 For this purpose, various layers of information such as biological results and/or taxonomic data have been used to discriminate specic ion clusters to allow for the in ne targeting the isolation of structurally new bioactive NPs. 10 Results of the biological screening of extracts using a chikungunya virus (CHIKV) cell-based assay and an oncogenic Wnt signalling assay were mapped to the MN, and colour tags were applied depending on the IC 50 or EC 50 values obtained.…”