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2020 Madden_Chemrxiv.pdf (5.29 MB)

A Pharmacophore-Based Approach to Demonstrating the Scope of Alcohol Dehydrogenases

submitted on 23.10.2020, 07:58 and posted on 23.10.2020, 12:25 by Katrina Madden, Peter M.T. Todd, Kouji Urata, Angela Russell, Kylie Vincent, Holly Reeve

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 publically available structures. We hope that this work, combined with our simple protocols for scaleable H2-driven biocatalytic ketone reduction, will facilitate a culture shift towards adopting biocatalysis alongside traditional chemical catalytic methods.


New routes to driving enzyme-catalysed chemical synthesis using hydrogen gas

Engineering and Physical Sciences Research Council

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Email Address of Submitting Author


Department of Chemistry, University of Oxford


United Kingdom

ORCID For Submitting Author


Declaration of Conflict of Interest