DNA‐Encoded Dynamic Combinatorial Chemical Libraries

Dynamic combinatorial chemistry (DCC) explores the thermodynamic equilibrium of reversible reactions. Its application in the discovery of protein binders is largely limited by difficulties in the analysis of complex reaction mixtures. DNA‐encoded chemical library (DECL) technology allows the selection of binders from a mixture of up to billions of different compounds; however, experimental results often show low a signal‐to‐noise ratio and poor correlation between enrichment factor and binding affinity. Herein we describe the design and application of DNA‐encoded dynamic combinatorial chemical libraries (EDCCLs). Our experiments have shown that the EDCCL approach can be used not only to convert monovalent binders into high‐affinity bivalent binders, but also to cause remarkably enhanced enrichment of potent bivalent binders by driving their in situ synthesis. We also demonstrate the application of EDCCLs in DNA‐templated chemical reactions.     

Computer Aided Analysis of Split and Mix Combinatorial Libraries

Combinatorial chemistry using split and pool synthesis involves making and testing mixtures of compounds in pools which are subsets of the larger compound collection. These subsets are created during the synthesis of the collection through a resin splitting and mixing method. Tests are conducted on each of the final pools of mixtures and the individual compounds within a mixture of interest are then identified through some deconvolution scheme, originally involving selective re-synthesis. It is possible that different schemes for splitting and mixing will have different consequences on the overall effort necessary to deconvolute interesting mixtures. The evaluation of different protocols of splitting and mixing involves consideration of more possibilities than can be exhaustively or optimally determined manually in a realistic time frame for most compound collections. We present herein a computational scheme to aid in this analysis. The approach exhaustively examines possible splitting and mixing strategies for the interrelated values of total library size, number of combinatorial steps, number of reaction vessels, and number of compounds per final pool. Weighting factors may be introduced into the various steps. The resulting complete list of splitting and mixing options is scored based on a variable weighting strategy for the total effort of synthesis and deconvolution. The results indicate the splitting/mixing strategy used has an impact on overall efficiency and should be considered in the design of compound libraries.     

Parallel Analysis of the Reaction Products from Combinatorial Catalyst Libraries

No Abstract     

Selecting Agonists from Single Cells Infected with Combinatorial Antibody Libraries

1. Download : Download high-res image (130KB)
2. Download : Download full-size image

     

利用亲和选择筛选法从组合化学库中筛选新药

组合化学方法可以产生大量的新化合物供新药筛选,但传统的逐一筛选法不能满足如此数量庞大的化合物,因此,针对混合物进行筛选显得非常重要,亲和选择筛选法利用药物作用的靶蛋白与潜在药物之间的亲和活性,使目标化合物与大量无亲和活性的化合物分离,然后只对有亲和活性的化合物进行结构鉴定,从而快速地从大量混合物中找到目标化合物,本文着重讨论了亲和选择筛选的的几种形,相应技术和在组合化学库筛选中的应用,亲和选择筛选大体分为两种方式：一种是将靶蛋白固定在支持物上,有亲和活力的化合物被保留,大量非亲和化合物被洗掉,另一种是在溶液中靶蛋白与混合物库孵育,然后利用受体配基复合物与不结合的游离化合性质的判别进行区分,亲和选择筛选法也适合于化合物的种类和含量都未知的天然提取物的筛选。     

Prevention of Cell Death by Antibodies Selected from Intracellular Combinatorial Libraries

1. Download : Download high-res image (88KB)
2. Download : Download full-size image

     

基于结构的组合库设计策略在新药创制中的应用

合理设计一些容量小的、针对特定靶标的化合物库(称为集中库,focused library),是当前组合库设计中的热点。当靶标的三维结构可以通过X射线衍射或NMR等手段确定后,人们就能采用几种不同的策略来进行组合库的设计。本文讨论了在靶标结合位点的约束下,进行组合库设计的主要方法及程序,同时强调了它们的优点与不足。通过这些方法的成功应用实例,显示了它们在新药创制中的广泛应用前景。     

Synthesis and Screening of Stereochemically Diverse Combinatorial Libraries of Peptide Tertiary Amides

1. Download : Download high-res image (275KB)
2. Download : Download full-size image

Highlights? A convenient synthesis of libraries of conformationally-constrained N-substituted oligoalanines ? A screen of such a library provided much higher affinity hits than a library of peptoids lacking c-alpha substitution ? Analysis of the isolated protein ligands demonstrated that the stereochemistry of the chiral centers was important ? These libraries should be a useful source of high affinity protein ligands     

Synthesizing Macrocycles under Thermodynamic Control – Dynamic Combinatorial Libraries and Templates

An effective way to synthesize macrocycles using a dynamic combinatorial library is demonstrated for the reaction of pyridine-2,6-dicarbaldehydes with several long diamines. According to the template ions present, a given library can be shifted towards several macrocycles as desired.     

Decoding Split and Pool Combinatorial Libraries with Electron-Transfer Dissociation Tandem Mass Spectrometry

Screening of bead-based split and pool combinatorial chemistry libraries is a powerful approach to aid the discovery of new chemical compounds able to interact with, and modulate the activities of, protein targets of interest. Split and pool synthesis provides for large and well diversified chemical libraries, in this case comprised of oligomers generated from a well-defined starting set. At the end of the synthesis, each bead in the library displays many copies of a unique oligomer sequence. Because the sequence of the oligomer is not known at the time of screening, methods for decoding of the sequence of each screening “hit” are essential. Here we describe an electron-transfer dissociation (ETD) based tandem mass spectrometry approach for the decoding of mass-encoded split and pool libraries. We demonstrate that the newly described “chiral oligomers of pentenoic amides (COPAs)” yield non-sequence-specific product ions upon collisional activated dissociation; however, complete sequence information can be obtained with ETD. To aid in the decoding of libraries from MS and MS/MS data, we have incorporated ⁷⁹Br/⁸¹Br isotope “tags” to differentiate N- and C-terminal product ions. In addition, we have created “Hit-Find,” a software program that allows users to generate libraries in silico. The user can then search all possible members of the chemical library for those that fall within a user-defined mass error.      

HTS by NMR of Combinatorial Libraries: A Fragment-Based Approach to Ligand Discovery

1. Download : Download high-res image (246KB)
2. Download : Download full-size image

Highlights? HTS by NMR combines protein NMR and combinatorial chemistry to screen large libraries ? The approach is best suited to identify ligands to protein-protein interactions ? The method enables a rapid assessment of the druggability of a given target ? We applied the method to a test case and to derive potent and selective EphA4 ligands     

Carbohydrate-Based Peptido Mimetics. Synthesis of Two New Scaffolds for Combinatorial Libraries.

The recent utilisation of the glucopyranose ring as scaffold for the synthesis of a potent somatostatin agonist demonstrated the use of monosaccharides as viable templates in drug design.^2,3 Monosaccharide-based mimics provide enantiomerically pure, rigid moieties (able to give precise orientation of functional groups), with a high degree of oxygenation to assure water solubility.⁴ Moreover, carbohydrates exhibit a high combinatorial density. These advantages prompted us to synthesise new monosaccharide derivatives as carbohydrate scaffolds for potential drug design.     

动态组合化学研究进展及其在药物设计中的应用

动态组合化学利用可逆过程连接库内的各种组分,实现动态库的多样性.在库中加入靶标分子,通过分子识别、分子组装,诱导产生和靶标分子产生最强键合的化合物,推动化合物库的移动.介绍了动态组合化学的基本原理,并综述了近年来发现的动态可逆过程和动态组合化学在生物学、新药设计中的应用.