Many drug molecules contain isonitrile substituents; however, synthesizing these compounds remains challenging in organic chemistry. The isonitrile synthesizing enzyme ScoE utilizes a substrate with the γ-Gly substituent, and using two molecules of dioxygen and α-ketoglutarate converts it to an isonitrile group through an oxidative decarboxylation reaction. To explore its substrate scope and whether this process could be used for the biosynthesis of isonitrile-containing drug molecules, we performed a predictive computational study. We started with the recent crystal structure coordinates of ScoE, removed the substrate and inserted two potential precursor molecules of the drug molecules axisonitrile-1 and xanthocillin into the structure, whereby both molecules have their isonitrile groups replaced by γ-Gly. Both substrates fit into the substrate binding pocket of the enzyme well and position them in the correct orientation for catalysis on the iron center. Based on a molecular dynamics simulation, we created a quantum chemical cluster model of the enzyme active site with γ-Gly-substituted axisonitrile-1 and studied the oxidative decarboxylation reaction to form axisonitrile-1 products. The calculations give similar barriers to wildtype substrate for either the initial C-H or N-H hydrogen atom abstraction, which leads to a radical intermediate and form desaturated reactants. We then took the desaturated substrate and created another iron(IV)-oxo model complex to study the subsequent hydrogen atom abstraction and decarboxylation and found this to be feasible as well although we predict to see by-products for hydroxylation in the second cycle. Nevertheless, we believe that the ScoE enzyme can be utilized for the biosynthesis of isonitrile substituents in substrates with γ-Gly components as an environmentally benign alternative to organic chemistry approaches for the synthesis of isonitrile groups. We hope that experimental studies will be able to confirm our hypothesis.