Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery

Anverenes B–E, New Polyhalogenated Monoterpenes from the Antarctic Red Alga <i>Plocamium cartilagineum</i>

The subtidal red alga Plocamium cartilagineum was collected from the Western Antarctic Peninsula during the 2011 and 2017 austral summers. Bulk collections from specific sites corresponded to chemogroups identified by Young et al. in 2013. One of the chemogroups yielded several known acyclic halogenated monoterpenes (2&#8211;5) as well as undescribed compounds of the same class, anverenes B&#8211;D (6&#8211;8). Examination of another chemogroup yielded an undescribed cyclic halogenated monoterpene anverene E (9) as its major secondary metabolite. Elucidation of structures was achieved through one-dimensional (1D) and 2D nuclear magnetic resonance (NMR) spectroscopy and negative chemical ionization mass spectrometry. Compounds 1&#8211;9 show moderate cytotoxicity against cervical cancer (HeLa) cells

Keikipukalides, Furanocembrane Diterpenes from the Antarctic Deep Sea Octocoral \u3cem\u3ePlumarella delicatissima\u3c/em\u3e

During a 2013 cruise in the Southern Ocean we collected specimens of the octocoral Plumarella delicatissima between 800 and 950 m depth. Five new furanocembranoid diterpenes, keikipukalides A–E (1–5), the known diterpene pukalide aldehyde (6), and the known norditerpenoid ineleganolide (7) were isolated from the coral. These Plumarella terpenes lack mammalian cytotoxicity, while 2–7 display activity against Leishmania donovani between 1.9 and 12 μM. Structure elucidation was facilitated by one- and two-dimensional NMR spectroscopy and mass spectrometry, and keikipukalides A and E were confirmed by X-ray crystallography

Darwinolide, a New Diterpene Scaffold That Inhibits Methicillin-Resistant <i>Staphylococcus aureus</i> Biofilm from the Antarctic Sponge <i>Dendrilla membranosa</i>

A new rearranged spongian diterpene, darwinolide, has been isolated from the Antarctic Dendroceratid sponge <i>Dendrilla membranosa</i>. Characterized on the basis of spectroscopic and crystallographic analysis, the central seven-membered ring is hypothesized to originate from a ring-expansion of a spongian precursor. Darwinolide displays 4-fold selectivity against the biofilm phase of methicillin-resistant <i>Staphylococcus aureus</i> compared to the planktonic phase and may provide a scaffold for the development of therapeutics for this difficult to treat infection

Keikipukalides, Furanocembrane Diterpenes from the Antarctic Deep Sea Octocoral <i>Plumarella delicatissima</i>

During a 2013 cruise in the Southern Ocean we collected specimens of the octocoral <i>Plumarella delicatissima</i> between 800 and 950 m depth. Five new furanocembranoid diterpenes, keikipukalides A–E (<b>1</b>–<b>5</b>), the known diterpene pukalide aldehyde (<b>6</b>), and the known norditerpenoid ineleganolide (<b>7</b>) were isolated from the coral. These <i>Plumarella</i> terpenes lack mammalian cytotoxicity, while <b>2</b>–<b>7</b> display activity against <i>Leishmania donovani</i> between 1.9 and 12 μM. Structure elucidation was facilitated by one- and two-dimensional NMR spectroscopy and mass spectrometry, and keikipukalides A and E were confirmed by X-ray crystallography