Docking is an important tool for probing protein function as it can identify both binding sites and molecules that can bind proteins and thus perturb protein function. Docking studies performed by the Snyder research group have identified anti-inflammatory adenosine receptor (AR) binders that also bind SARS-CoV2 non-structural protein 16 (nsp16) as well as the presence of a binding pocket on tyrosinase capable of catalyzing a key step in lipofuscin formation. SARS-CoV2 nsp16 is a methyltransferase that prevents the innate immune response from detecting SARS-CoV2 replication: inhibiting nsp16 with an AR agonist ensures the innate immune system detects SARS-CoV2 replication while preventing hyperinflammation. Lipofuscin is an, oftentimes, fluorescent pigment, produced by reactions between polyunsaturated fatty acid (PUFA) oxidation products with other biological molecules. Lipofuscin accumulates as cells age and increased lipofuscin formation is associated with diseases including Parkinson’s disease. Since Parkinson’s disease involves neurons characterized by (neuro) melanin, we investigated the influence of tyrosinase, the enzyme catalyzing the initial reactions involved in melanin formation, on lipofuscin formation. Docking studies verify experimental results demonstrating that tyrosinase catalyzes a Hantzsch pyrimidine synthesis as well as results with an <i>in vitro</i> model of lipofuscin formation. These docking studies identify binding pockets, distal from the tyrosinase active site, in both human and mushroom tyrosinase potentially catalyzing a condensation reaction between acetoacetone and propanal. Tyrosinase’s ability to catalyze condensation reactions between reactive carbonyl compounds points to a role for tyrosinase in detoxifying reactive aldehydes, produced from PUFA oxidation.

Docking studies on SARS-CoV2 nsp16 and tyrosinase: Repurposing drugs and discovery of novel enzymatic activities

ACS Spring Meeting 2021

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