Abstract
Phylum Cnidaria has been an excellent source of natural products, with thousands of metabolites identified. Many of these have not been screened in bioassays. The aim of this study was to explore the potential of 5600 Cnidaria natural products (after excluding those known to derive from microbial symbionts), using a systematic approach based on chemical space, drug-likeness, predicted toxicity, and virtual screens. Previous drug-likeness measures: the rule-of-five, quantitative estimate of drug-likeness (QED), and relative drug likelihoods (RDL) are based on a relatively small number of molecular properties. We augmented this approach using reference drug and toxin data sets defined for 51 predicted molecular properties. Cnidaria natural products overlap with drugs and toxins in this chemical space, although a multivariate test suggests that there are some differences between the groups. In terms of the established drug-likeness measures, Cnidaria natural products have generally lower QED and RDL scores than drugs, with a higher prevalence of metabolites that exceed at least one rule-of-five threshold. An index of drug-likeness that includes predicted toxicity (ADMET-score), however, found that Cnidaria natural products were more favourable than drugs. A measure of the distance of individual Cnidaria natural products to the centre of the drug distribution in multivariate chemical space was related to RDL, ADMET-score, and the number of rule-of-five exceptions. This multivariate similarity measure was negatively correlated with the QED score for the same metabolite, suggesting that the different approaches capture different aspects of the drug-likeness of individual metabolites. The contrasting of different drug similarity measures can help summarise the range of drug potential in the Cnidaria natural product data set. The most favourable metabolites were around 210–265 Da, quite often sesquiterpenes, with a moderate degree of complexity. Virtual screening against cancer-relevant targets found wide evidence of affinities, with Glide scores <−7 in 19% of the Cnidaria natural products.
Highlights
The diversity of natural products presents a problem: the metabolites have potential in many therapeutic areas, but where does the potential lie? One route to defining applications for natural products is through bioassays
We focus on Cnidaria-derived natural products (NPs)
Cnidaria NPs (n = 5600), drugs (n = 2009) and a reference set of active, non-drug molecules (‘toxic’, n = 2012) do not appear to be separate in the first two dimensions of a PCA based on QikProp generated properties (Figure 1)
Summary
The diversity of natural products presents a problem: the metabolites have potential in many therapeutic areas, but where does the potential lie? One route to defining applications for natural products is through bioassays. We focus on Cnidaria-derived natural products (NPs). The sources of natural products in both Porifera (sponges) and Cnidaria may, have a symbiont origin. Our current study excluded NPs known to have a symbiont origin. The marine natural product (NP) database MarinLit (http://pubs.rsc.org/marinlit, accessed in December 2018) has 5827 metabolites isolated from Cnidaria published in 1828 papers. By randomly taking 100 papers spread over the full period of records (1940–2018), we estimated that only 24% of papers screened one or several metabolites against one or a few human diseases. This implies that Cnidaria NP potential bioactivity is under-explored
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