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.

中文翻译：

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基于药理学的方法来证明酒精脱氢酶的范围

解决了将早期生物化学催化不对称合成用于早期药物化学的障碍，该方法使用醇脱氢酶还原酮作为模型反应。一种有效的底物筛选方法用于显示商业酒精脱氢酶的广泛底物范围，对观察到的药物发现中使用的化学基团（杂环，三氟甲基和腈/硝基）具有很高的耐受性。我们使用我们的筛选数据，使用精度为0.67 / 1的Forge软件，构建基于药效团的初步预测性筛选工具，证明了开发可用于商业酶的底物筛选工具而不需要公开提供结构的潜力。我们希望这项工作与我们可扩展H2驱动的生物催化酮还原的简单方案相结合，