Mining Medicinally Relevant Bioreduction Substrates Inspired by Ligand-Based Drug Design,Journal of Medicinal Chemistry

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Mining Medicinally Relevant Bioreduction Substrates Inspired by Ligand-Based Drug Design
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-25 , DOI: 10.1021/acs.jmedchem.4c01129
Alexander J Rago ₁ , Ioanna Zoi ₁ , Jackson A Gartman ₁ , Kelly A McDaniel ₁ , Navendu Jana ₁ , Dachun Liu ₁ , Wen-Ju Bai ₁

Affiliation

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.

中文翻译：

受基于配体的药物设计的启发，挖掘医学相关的生物还原底物

在没有酶结构的情况下探索生物催化转化的范围而不进行大量的实验是一项具有挑战性的任务。为了扩大胡萝卜介导的生物还原的有限底物容量，并以最低的劳动力和时间成本寻找新的医学相关酮，我们采用了一种受基于配体的药物设计启发的实用方法。通过分析收集的文献数据并建立药效团和反应性预测模型，我们筛选了一个自建的超过 8000 个酮的虚拟库，其中包含药物发现中最常用的N、O、S杂环和官能团。验证了代表性实例，扩大了生物还原底物范围。我们的模型的公开可用性以及简单的筛选工作流程使得可以节省时间、劳动力和成本来评估药物化学应用中的未知生物还原底物，特别是对于大量结构差异的酮。我们的研究还展示了利用药物化学原理解决一般生物催化问题的新颖性。

更新日期：2024-07-25

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