A pharmacophore-based approach to demonstrating the scope of alcohol dehydrogenases

Barriers to the ready adoption of biocatalysis into asymmetric synthesis for early stage medicinal chemistry are addressed, using ketone reduction by alcohol dehydrogenase as a model reaction. An efficient substrate screening approach is used to show the wide substrate scope of commercial alcohol dehydrogenase enzymes, with a high tolerance to chemical groups employed in drug discovery (heterocycle, trifluoromethyl and nitrile/nitro groups) observed. We use our screening data to build a preliminary predictive pharmacophore-based screening tool using Forge software, with a precision of 0.67/1, demonstrating the potential for developing substrate screening tools for commercially available enzymes without publicly available structures. We hope that this work will facilitate a culture shift towards adopting biocatalysis alongside traditional chemical catalytic methods in early stage drug discovery.

Automated summary

Barriers to the adoption of biocatalysis in early stage medicinal chemistry are addressed using ketone reduction as a model reaction. Commercial alcohol dehydrogenase enzymes show wide substrate scope and high tolerance to chemical groups commonly used in drug discovery. A preliminary predictive pharmacophore-based screening tool is developed using substrate screening data, demonstrating the potential for developing such tools for commercially available enzymes without publicly available structures.