Department of Chemistry, Section of Organic Chemistry and Biochemistry, University of Ioannina, 45110 Ioannina, Greece; Department of Biological Applications and Technologies, University of Ioannina, 45110 Ioannina, Greece.
Department of Chemistry, Section of Organic Chemistry and Biochemistry, University of Ioannina, 45110 Ioannina, Greece.
Biochim Biophys Acta Gen Subj. 2018 Jan;1862(1):1-8. doi: 10.1016/j.bbagen.2017.09.021. Epub 2017 Sep 30.
Natural products offer a wide range of biological activities, but they are not easily integrated in the drug discovery pipeline, because of their inherent scaffold intricacy and the associated complexity in their synthetic chemistry. Enzymes may be used to perform regioselective and stereoselective incorporation of functional groups in the natural product core, avoiding harsh reaction conditions, several protection/deprotection and purification steps.
Herein, we developed a three step protocol carried out inside an NMR-tube. 1st-step: STD-NMR was used to predict the: i) capacity of natural products as enzyme substrates and ii) possible regioselectivity of the biotransformations. 2nd-step: The real-time formation of multiple-biotransformation products in the NMR-tube bioreactor was monitored in-situ. 3rd-step: STD-NMR was applied in the mixture of the biotransformed products to screen ligands for protein targets.
Herein, we developed a simple and time-effective process, the "NMR-tube bioreactor", that is able to: (i) predict which component of a mixture of natural products can be enzymatically transformed, (ii) monitor in situ the transformation efficacy and regioselectivity in crude extracts and multiple substrate biotransformations without fractionation and (iii) simultaneously screen for interactions of the biotransformation products with pharmaceutical protein targets.
We have developed a green, time-, and cost-effective process that provide a simple route from natural products to lead compounds for drug discovery.
This process can speed up the most crucial steps in the early drug discovery process, and reduce the chemical manipulations usually involved in the pipeline, improving the environmental compatibility.
天然产物具有广泛的生物活性，但由于其固有结构的复杂性和相关合成化学的复杂性，它们不易被整合到药物发现的管道中。酶可以用于在天然产物核心中进行区域和立体选择性的官能团引入，避免使用苛刻的反应条件、多次保护/脱保护和纯化步骤。
本文开发了一种在 NMR 管内进行的三步法。第一步：STD-NMR 用于预测：i）天然产物作为酶底物的能力，ii）生物转化的可能区域选择性。第二步：在 NMR 管生物反应器中实时监测多种生物转化产物的形成。第三步：STD-NMR 应用于生物转化产物的混合物中，筛选针对蛋白靶标的配体。
本文开发了一种简单有效的方法，即“NMR 管生物反应器”，能够：（i）预测混合物中哪些天然产物成分可以被酶转化，（ii）原位监测粗提取物和多种底物生物转化的转化效率和区域选择性，而无需进行分离，（iii）同时筛选生物转化产物与药物蛋白靶标的相互作用。
我们开发了一种绿色、省时、低成本的工艺，为从天然产物到药物发现的先导化合物提供了一条简单的途径。
该工艺可以加速药物发现早期过程中最关键的步骤，并减少管道中通常涉及的化学操作，提高环境相容性。
