摘要：2024年11月28日，北京——纽卡斯尔大学的Michael Waring教授做客康龙化成第五十一期“合成与药物化学前沿”名师线上讲座，报告主题为“使用小分子碎片和DNA编码库发现苗头化合物的新方法”。报告重点介绍了：1）利用氢键相互作用自主研发的小分子碎片库

转自：康龙化成

康龙化成举办第五十一期“合成与药物化学前沿”名师线上讲座

2024年11月28日，北京——纽卡斯尔大学的Michael Waring教授做客康龙化成第五十一期“合成与药物化学前沿”名师线上讲座，报告主题为“使用小分子碎片和DNA编码库发现苗头化合物的新方法”。报告重点介绍了：1）利用氢键相互作用自主研发的小分子碎片库（命名为FragLites），在辨识蛋白质中药物作用靶点的应用；2）在合成DNA编码库中，利用胶束催化各类常见有机化学反应；3）DNA编码库的小分子碎片扩增技术（NUDELs）在BRD4蛋白中的应用案例。

首先，Michael Waring教授介绍了目前使用化合物库技术筛选药物的局限性。以此作为出发点，他们小组发展了新的小分子碎片库（FragLites）技术。在该技术中，利用小分子中的氢键供体/受体相互作用，碎片库中的某些分子能够与蛋白质中的潜在成药性位点进行结合。同时，在小分子碎片库中，所有分子都含有卤素原子作为标记，使得它们能够在X光衍射中被识别出来，这样就可以识别出与特定小分子相结合的蛋白质位点，并根据小分子的结构特点进行药物设计，减少筛选化合物库的合成工作，提高筛选的命中率。Waring教授在CDK2、BRD4和ATAD2三种蛋白中对比了该方法与传统方法，验证了该方法的实用性。

然后，Michael Waring教授介绍了胶束催化常见有机反应的技术在合成DNA编码库中的应用。DNA编码库合成过程中，对原料的转化率有很高的要求，但是水相的反应环境以及DNA标记对传统有机反应条件的敏感性，导致原料无法完全转化。胶束末端的疏水基团能够在水溶液体系中创造出微小的疏水环境，使DNA链末端的小分子底物能够进入该疏水环境。通过优化反应的各项参数，如催化剂、浓度、溶剂、当量和温度等，在DNA编码库的合成中，实现了高效的Suzuki-Miyaura、Buchwald-Hartwig、酰胺缩合、还原胺化、Heck偶联、Sonogashira偶联和芳香亲核取代反应。

最后，Michael Waring教授展示了定向的DNA编码库小分子碎片扩增技术（NUDELs）。在BRD4蛋白中，Waring教授结合他们改进的DNA编码库合成技术（NUDELs）和小分子碎片库（FragLite）技术，通过连接特定小分子片段到DNA编码库末端，增强了特定化合物与BRD4蛋白中结合位点的亲和力，使它达到能够成药的水平。

会后，Michael Waring教授在问答环节中与听众进行了热烈的讨论。

Frontiers in Synthetic and Medicinal Chemistry

--The 51st Pharmaron Virtual Lecture

Beijing,China, November 28, 2024 - Pharmaron held its 51st virtuallecture in the Frontiers of Synthetic and Medicinal Chemistry series, which wasdelivered by Prof. Michael Waring from Newcastle University. The presentation wastitled “New Approaches to HitGeneration Using Fragments and DNA-encoded Libraries.” The talk focusedon three areas: 1) The application of the small molecule fragment library(named FragLites) independently developed by the group using hydrogen bondinteractions to identify binding sites in proteins; 2) micelles catalysisapplied in organic reactions in DNA-encoded libraries (named DELs); 3) Thetechnique of fragment expansion in DELs (named NUDELs) and its application inBRD4 protein.

First, Professor Michael Waring discussed the limitationsof finding ligand binding sites in proteins using the traditional High-ThroughputScreening (HTS) method. Accordingly, his group developed a novel technologymapping the interaction site with small molecule fragments (FragLites). In thisnew method, the drug-like interactions would be identified productively throughhydrogen-bond donor/acceptor interactions from these small fragments. At thesame time, incorporating a heavy halogen atom into each compound would furtherallow unambiguous identification of the position and orientation of thefragments by detecting a signal in X-ray crystallography that arises from the anomalousdispersion of the halogen atom. The drug design could then be carried outaccording to the structural characteristics of these fragments, reducing the largeamounts of synthesis of the lead-like libraries and improving the efficiencyand hit rate. Professor Waring compared the method with traditional HTS inCDK2, BRD4 and ATAD2 proteins to verify the practicability of this method.

Professor Michael Waring then presented the application of micellar catalysis for common organic reactions in DNA-encoded libraries (DELs). There has always been a high conversion request for DELs. However, the environment of aqueous phase and the sensitivity of DNA tags to traditional organic reaction conditions has led to incomplete transformation of substrates. The hydrophobic tails at the end of micelles could create a tiny hydrophobic environment in the aqueous solution system for the organic reactions of the small molecular substrates at the end of DNA strands. By optimizing various reaction parameters, such as catalyst, concentration, solvent, equivalent and temperature, efficient Suki-Miyaura, Buchwald-Hartwig, amide condensation, reductive amination, Heck, Sonogashira and SNAr, reactions were realized in the synthesis of DNA-encoded libraries.

Finally,Professor Michael Waring presented a case for combining these two approaches todrug discovery. In the BRD4 protein, poised DNA-encoded chemical libraries(NUDELs), together with the FragLites technique, his group was able tosuccessfully enhance the affinity of a weak binding fragment at the end of theDNA-tag to the binding sites in BRD4 protein by attaching another specificsmall molecule fragment to reach a drug-like level.

Followingthe presentation, Prof. Michael Waring engagedin a Q&A session with the audience.

来源：新浪财经