Natural products have long been a productive source of drug leads for the development of new therapies including anti-infectives and anti-cancer agents. Identifying potential targets of these natural products may assist in designing more tolerable treatments for a range of diseases. One such target may be the ADP-ribosyl transferase member 8 (ARTD8, alternatively named PARP14, BAL2 and COAST6), a post-translational modifier enzyme with an associated role in promoting disease-progression in many cancers, including prostate and hepatocellular cancer. However, there is currently a lack of experimental evidence to prove the association between natural products and ARTD8 inhibition.
Actives from natural products with a documented anti-cancer activity were docked into the catalytic site of 3SMI.pdb using PyRx and AutoDock Vina. Lead compounds from the docking studies were also assessed for their in vitro activity against ARTD8 at 20 mM and 10 mM concentrations.
In silico docking revealed epigallocatechin gallate (EGCG), trans-resveratrol, indol-3-carbinol, curcumin, quercetin, and naringenin as potential ARTD8 inhibiting compounds. The subsequent in vitro assay revealed EGCG and quercetin as lead compounds, with EGCG displaying complete inhibition at 10 mM. Both EGCG and quercetin docked poses where shown to span across the nicotinamide and adenine sub-sites of the catalytic domain, interacting with conserved residues Ser1641 and/or Ser1607 and Tyr1646 of ARTD8.
The in silico docking and in vitro studies present both EGCG and quercitin as potential ARTD8 inhibiting compounds. Structural analysis of these leads also suggests that the meta-hydroxy group on the catechin ring B backbone maybe responsible for these inhibition effects.
|Publication status||Published - 14 Oct 2020|
|Event||2020 Bond University HSM Medical & Postgraduate Students Research Virtual Conference: Fostering healthcare innovations and resilience - Online, Australia|
Duration: 14 Oct 2020 → 14 Oct 2020
|Conference||2020 Bond University HSM Medical & Postgraduate Students Research Virtual Conference|
|Period||14/10/20 → 14/10/20|