Tuaimenal A, a Meroterpene from the Irish Deep-Sea Soft Coral Duva florida, Displays Inhibition of the SARS-CoV-2 3CLpro Enzyme.

Cold water benthic environments are a prolific source of structurally diverse molecules with a range of bioactivities against human disease. Specimens of a previously chemically unexplored soft coral, Duva florida, were collected during a deep-sea cruise that sampled marine invertebrates along the Irish continental margin in 2018. Tuaimenal A (1), a cyclized merosesquiterpenoid representing a new carbon scaffold with a highly substituted chromene core, was discovered through exploration of the soft coral secondary metabolome via NMR-guided fractionation. The absolute configuration was determined through vibrational circular dichroism. Functional biochemical assays and in silico docking experiments found tuaimenal A selectively inhibits the viral main protease (3CLpro) of SARS-CoV-2.

Not Drug-like, but Like Drugs: Cnidaria Natural Products.

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.