In 2000, a novel secondary metabolite (erebusinone) was isolated from the Antarctic sponge, <i>Isodictya erinacea</i>. It was observed that the sponge remained free from predation despite a lack of defense spicules. This led to the hypothesis that protection was derived from secondary metabolites. The bioactivity of erebusinone was investigated and found to inhibit molting of the small arthropod Orchomene plebs. Xanthurenic acid (XA) is a known endogenous molt inhibitor present in arthropods. Structural similarities between XA and erebusinone prompted the hypothesis that their modes of action to inhibit the production of the circulating molting hormone (20-hydroxyecdysone) may be the same. Previous experimental studies have predicted that XA inhibits one of two P450 enzymes (CYP315a1, CYP314a1) that are responsible for the final two hydroxylations in the production of 20E. Lack of crystal structures and biochemical assays for these marine arthropod P450s has prevented experimental exploration of this ecological interaction. Herein, a wide array of computational techniques (homology modeling, molecular dynamics simulations, binding site bioinformatics, and flexible receptor - flexible ligand docking) have been employed to elucidate the structure - function relationships for substrate/product and aromatic small molecule inhibitors (XA, erebusinone, 3-hydroxy-L-kynurenine) of the aforementioned P450s. Further, the final docked poses were subjected to 4 ns of MD simulations and per-residue energy decomposition analysis were performed on the representative members of the most highly populated (determined via clustering analysis) conformations. Results indicate that xanthurenic acid and erebusinone would most likely inhibit CYP315a1, primarily driven by aromatic interactions with the protein active site residues. However, 3-hydroxy-L-kynurenine may preferentially bind CYP314a1, though upon binding it may face desolvation penalties in order to disrupt pre-existing electrostatic interactions.

Elucidating a chemical defense mechanism of Antarctic sponges

249th National Meeting (2015)

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