Mining Medicinally Relevant Bioreduction Substrates Inspired by Ligand-Based Drug Design

Exploring the scope of biocatalytic transformations in
the absence
of enzyme structures without extensive experimentation is a challenging
task. To expand the limited substrate capacity of carrot-mediated
bioreduction and hunt for new medicinally relevant ketones with minimum
cost of labor and time, we deployed a practical method inspired by
ligand-based drug design. Through analyzing collected literature data
and building pharmacophore and reactivity prediction models, we screened
a self-built virtual library of >8000 ketones bearing the most
frequently
used N,O,S-heterocycles and functional groups in
drug discovery. Representative examples were validated, expanding
the bioreduction substrate scope. The public availability of our models
alongside the straightforward screening workflow makes it time-, labor-,
and cost-saving to evaluate unknown bioreduction substrates for medicinal
chemistry applications, especially for a large set of structurally
differentiated ketones. Our studies also showcase the novelty of utilizing
medicinal chemistry principles to solve a general biocatalysis problem.