Glycopeptide and Oligosaccharide Libraries

Despite the burgeoning interest in the various biological functions and consequent therapeutic potential of the vast number of oligosaccharides found in nature on glycoproteins and cell surfaces, the development of combinatorial carbohydrate chemistry has not progressed as rapidly as expected. The reason for this imbalance is rooted in the difficulty of oligosaccharide assembly and analysis that renders synthesis a rather cumbersome endeavor. Parallel approaches that generate series of analogous compounds rather than real libraries have therefore typically been used. Since generally low affinity is obtained for interactions between carbohydrate receptors and modified oligosaccharides designed as mimetics of natural carbohydrate ligands, glycopeptides have been explored as alternative mimics. Glycopeptides have been proven in many cases to be superior ligands with higher affinity for a receptor than the natural carbohydrate ligand. High-affinity glycopeptide ligands have been found for several types of receptors including the E-, P-, and L-selectins, toxins, glycohydrolases, bacterial adhesins, and the mannose-6-phosphate receptor. Furthermore, the assembly of glycopeptides is considerably more facile than that of oligosaccharides and the process can be adapted to combinatorial synthesis with either glycosylated amino acid building blocks or by direct glycosylation of peptide templates. The application of the split and combine approach using ladder synthesis has allowed the generation of very large numbers of compounds which could be analyzed and screened for binding of receptors on solid phase. This powerful technique can be used generally for the identification and analysis of the complex interaction between the carbohydrates and their receptors.     

Assembly of Oligosaccharide Libraries

Carbohydrates contain an evolutionary potential of information content several orders of magnitude higher in a short sequence than any other biological oligomer due to their monomers capable of more than one linkage position, anomerity, and branching. It has been well-documented that the structural diversity of sugar oligomers leads to their involvement in many key inter-and intracellular events. Cells, bacteria, viruses, and toxins often use cell-surface carbohydrates as points of attachment. These and other important discoveries in molecular glycobiology have stimulated intense research in oligosaccharides, focusing on both their synthesis and structure-function relationship study.     

Construction and Analysis of N-phosphoryl Peptide Libraries

N-Phosphoryl peptide libraries were constructed by transformation from homo-oligopeptide libraries, which was synthesized by self-assembly of amino acids with the assistance of phosphorus oxychloride. Electrospray ionization mass spectrometry (ESI-MS) was used to monitor the reaction.     

Extending the Substrate Scope for the Asymmetric Iridium‐Catalyzed Hydrogenation of Minimally Functionalized Olefins by Using Biaryl Phosphite‐Based Modular Ligand Libraries

Asymmetric hydrogenation is one of the most efficient and atom‐economical tools to prepare chiral molecules. However, the enantiodiscrimination of simple, minimally functionalized olefins is still challenging and requires more sophisticated ligand design. Herein, we discuss our progress in the successful development of ligand design for the iridium‐catalyzed asymmetric hydrogenation of minimally functionalized olefins.

     

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.     

The Design of Leadlike Combinatorial Libraries

The optimization of low-potency leads into drugs is often accompanied by an increase in molecular weight (M(r)) and lipophilicity, as a consequence of affinity enhancement. Hits with affinity at μM levels discovered by screening leadlike libraries allow scope for this optimization process, as shown schematically by the distributions of M(r) for a leadlike library (1), oral drugs (2), and a typical combinatorial chemistry library (3). y=percentage with a particular molecular weight.     

Libraries via Metathesis of Internal Olefins

The cross-metathesis of internal olefins is applied for the combinatorial synthesis of small organic molecules; this reaction is conveniently carried out in neat olefin (oleic-acid derivatives) and requires only 0.001 equiv. of [Ru(CHPh)Cl₂(PCy₃)₂] as catalyst (Cy = cyclohexyl).     

组合化学、分子库与新药研究

组合化学是进入90 年代以来寻找及优化新药先导化合物的主要研究方法, 其特点是改变了传统的逐一合成、逐一纯化、逐一筛选的模式, 而是以合成和筛选化学库的形式完成寻找及优化药物先导化合物, 极大地加快了药物先导化合物出现的速度。本文就目前有关组合化学研究的基本理论、基本方法、发展趋势、研究成果以及我国应当采取的措施进行了综述。     

Secondary Structure Libraries for Artificial Evolution Experiments

Methods of artificial evolution such as SELEX and in vitro selection have made it possible to isolate RNA and DNA motifs with a wide range of functions from large random sequence libraries. Once the primary sequence of a functional motif is known, the sequence space around it can be comprehensively explored using a combination of random mutagenesis and selection. However, methods to explore the sequence space of a secondary structure are not as well characterized. Here we address this question by describing a method to construct libraries in a single synthesis which are enriched for sequences with the potential to form a specific secondary structure, such as that of an aptamer, ribozyme, or deoxyribozyme. Although interactions such as base pairs cannot be encoded in a library using conventional DNA synthesizers, it is possible to modulate the probability that two positions will have the potential to pair by biasing the nucleotide composition at these positions. Here we show how to maximize this probability for each of the possible ways to encode a pair (in this study defined as A-U or U-A or C-G or G-C or G.U or U.G). We then use these optimized coding schemes to calculate the number of different variants of model stems and secondary structures expected to occur in a library for a series of structures in which the number of pairs and the extent of conservation of unpaired positions is systematically varied. Our calculations reveal a tradeoff between maximizing the probability of forming a pair and maximizing the number of possible variants of a desired secondary structure that can occur in the library. They also indicate that the optimal coding strategy for a library depends on the complexity of the motif being characterized. Because this approach provides a simple way to generate libraries enriched for sequences with the potential to form a specific secondary structure, we anticipate that it should be useful for the optimization and structural characterization of functional nucleic acid motifs.     

药物发现中常用化合物库特征描述与对比分析

随着计算技术的发展和分子模拟软件的日趋成熟, 虚拟筛选已经在药物发现过程中发挥着越来越重要的作用. 在虚拟筛选过程中, 所使用化合物库的质量对先导化合物发现的成功率起着至关重要的作用. 本文通过对已知药物库、天然产物库、中药原植物化学成分库、筛选常用商业化合物库以及研究者所在实验室建立的化合物库的分析比较, 从化合物库的分子多样性、化学空间和分子骨架等多个方面提取并对比每一种化合物库的特征, 发现了已知药物库与中药原植物化学成分库的特征相似性, 揭示了中药原植物化学成分库作为筛选库的类药性优势, 并且深化了对几种筛选用化合物库特征的认识和理解.     

Solid-Phase Synthesis and Encoding Strategies for Olefin Polymerization Catalyst Libraries

Active polymerization catalysts , novel resin-bound diimine complexes of nickel(II ) and palladium(II ) are obtained by combinatorial synthesis and combined in a catalyst library. By tagging with fluorescent markers, the catalysts can be coded. Therefore, after cleavage of the tag from the polymer-coated resin, HPLC can be used to determine the pathway along which the products were formed.