动态组合化学最新进展

动态组合化学是组合化学的一个新兴分支,在药物先导化合物的发现中有广阔的应用前景。在动态组合化学库中,利用靶标分子的诱导结合作用,通过可逆共价反应,能够选择性的筛选到与靶标分子存在强相互作用的优势化合物。本文按照动态组合化学方法简介、动态组合化学中的可逆共价化学、动态组合化学库的分类、动态组合化学库筛选方法的研究进展及动态组合化学在药物先导化合物发现过程中的应用等5个方面对动态组合化学进行了概述。     

化学信息学的涵义及教育

化学信息学是近年来发展起来的新学科 ,它的产生与发展是基于化学信息量指数般增长 ,特别是组合化学及高通量筛选的迅速发展。组合化学方法能像搭积木块一样快速合成及制备大量的化合物。一个组合化学库包括数百个至数十万个化合物 ,为药物开发提供丰富的化合物源。高通量筛选能达到 1× 1 0 4～ 1× 1 0 5 个化合物 /天。组合化学及高通量筛选为药物研制提供新的技术支柱 ,同时也为化学信息学的产生与发展提供良好的机遇。　　人类基因组计划为药物开发与疾病的治疗提供众多的新靶标。据 1 996年统计用于药物研制的靶标有 483个分子靶 (其…     

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。     

精制透骨消痛颗粒防治骨性关节炎的计算机药理学

采用分子相似性分析、化学空间、分子对接、生物网络技术和药代动力学性质预测等计算机药理学方法研究中药精制透骨消痛颗粒中514个化合物的药理学机制. 结果表明: 该复方所含化合物在化学结构上具有多样性及大部分化合物在化学空间上具有类药性质; 通过514 与35个骨性关节炎疾病相关的公认靶标的相互作用及它们在靶空间的分布上阐明了精制透骨消痛颗粒防治骨性关节炎的可能作用机理, 发现了一些潜在的活性分子; 通过分析药物库中骨性关节炎的药物-靶点的作用网络及精制透骨消痛颗粒中分子-靶点的作用网络的异质性值、特征路径长度等特征, 揭示精制透骨消痛颗粒的多药物、多靶点、多途径分子作用机制. 结果有助于理解中药精制透骨消痛颗粒的复杂作用机制.     

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.     

化学库及分子差异性设计研究进展

组合化学是近年来发展起来的一种快速合成和平行筛选群体化合物的新方法。它可以用来设计先导化合物，也可以对药物分子进行结构改造。本文主要综述了化学库的合成以及计算机辅助组合化学的研究进展。     

MALDI-TOF-MS用于组合化学肽库的鉴定

组合化学是一种快速制备大量相关化合物,并可快速对其进行生物活性筛选的革新性的技术和方法。组合化学法自问世以来在生命科学和医药科学技术等领域获得了飞速发展。组合化学肽库已成为同时制备大量不同序列多肽的方法,并已广泛用于抗原决定簇、生物分子相互作用、亲和抑制剂、新药筛选等研究。在亲和筛选研究中,合成组合肽库的评价以及结构鉴定是研究成败的关键步骤之一。     

固相有机合成小分子化合物库

从杂环化合物库和非杂环化合物库两方面介绍了组合化学中采用固相合成技术所构建的小分子化合物库。     

PPAR激动剂的定向设计、虚拟筛选及合成

过氧化物酶体增殖因子活化受体(PPAR)是核受体超家族的一员.基于受体结构的药物分子设计与组合化学策略相结合,构建了过氧化物酶体增殖因子活化受体(PPAR)激动剂的虚拟化合物库.将已知小分子配体(GW409544)与PPAR晶体复合物进行剥离,得到受体的活性构象,并利用此活性受体分子与虚拟库中小分子进行对接和虚拟筛选,得到理论上结合较强的化合物,并对这些化合物进行合成,共合成9个新化合物.活性筛选结果显示化合物对PPAR具有一定的亲和力,其中有三个化合物显示出对PPARα,PPARγ的双重激动作用,从而指导新活性化合物的设计和合成.     

化合物库的组合技巧和组合合成

从化合物库的组合技巧和组合合成方法两个方面探讨了组合化学及其在药物开发中的应用。     

Non-covalent capillary coatings for protein separations in capillary electrophoresis

Adsorption of proteins, particularly basic proteins onto fused silica capillaries severely degrades capillary electrophoretic performance. This review provides a synopsis of the fundamentals underlying protein adsorption and its impact on CE performance. The efficacy of small molecule background electrolyte additives, surfactants, physically adsorbed polymers (dynamic and static), and successive multiple ionic-polymer layer coatings are evaluated using a number of performance metrics. Peak efficiency and migration time reproducibility are used as measures of reversible protein adsorption, while protein recovery, electroosmotic flow reproducibility and step changes in the baseline are used as indicators of irreversible protein adsorption.     

镍铝催化剂吸附动力学参数的非线性动态分析

在推导出适应于甲烷化反应体系非线性动态分析不同吸附物种动力学参数模型的基础上，采用计算优化出工业镍铝甲烷化催化剂上可逆吸附氢和可逆吸附一氧化碳的吸附速率常数和吸附平衡常数。结果表明，镍铝催化剂上吸附可逆氢要比吸附一氧化碳快２．２倍左右。该结果为镍铝催化剂上甲烷化产物的生成主要依赖于一氧化碳的吸附这一判断提供了理论依据。由于镍铝催化剂上甲烷化是可逆吸附氢与不可逆吸附一氧化碳共同作用的结果，且不可逆吸     

Protein-Templated Fragment Ligations—From Molecular Recognition to Drug Discovery

Protein-templated fragment ligation is a novel concept to support drug discovery and can help to improve the efficacy of protein ligands. Protein-templated fragment ligations are chemical reactions between small molecules (“fragments”) utilizing a protein's surface as a reaction vessel to catalyze the formation of a protein ligand with increased binding affinity. The approach exploits the molecular recognition of reactive small-molecule fragments by proteins both for ligand assembly and for the identification of bioactive fragment combinations. In this way, chemical synthesis and bioassay are integrated in one single step. This Review discusses the biophysical basis of reversible and irreversible fragment ligations and gives an overview of the available methods to detect protein-templated ligation products. The chemical scope and recent applications as well as future potential of the concept in drug discovery are reviewed.     

Synthesis of Components for the Generation of Constitutional Dynamic Analogues of Nucleic Acids

The introduction of dynamic covalent polymers, in which the monomer units are linked by reversible covalent bonds and can undergo component exchange, opens up new possibilities for the generation of functional materials. Extending this approach to the generation of dynamic biopolymers in aqueous media, which are able to adapt constitution (sequence, length) to external factors (e.g., environment, medium, template), would provide an alternative approach to the de novo design of functional dynamic bio‐macromolecules. As a first step towards this goal, various mono‐ and bifunctionalised (hetero‐ and homotopic) nucleic acid‐derived building blocks of type I – X have been synthesised for the generation of dynamic main‐chain and side‐chain reversible nucleic acid analogues. Hydrazide‐ and/or acetal (protected carbonyl)‐functionalised components were selected, which differ in terms of flexibility, length, net formal charge, and hydrazide/acetal substituents, in order to explore how such factors may affect the properties (structure, solubility, molecular recognition features) of the polymer products that may be generated by polycondensation.     

Thermal denaturation of collagen analyzed by isoconversional method

An isoconversional method is proposed to be used for evaluating activation energy of protein denaturation. Applied to DSC data on collagen denaturation, the method yields an activation energy that decreases throughout the process. The Lumry-Eyring model gives an explanation for this decrease and affords estimates for the enthalpy of the reversible step and the activation energy of the irreversible step of denaturation. The reversible unfolding is detectable by multi-frequency temperature-modulated DSC.     

Beiträge zur Chemie der Pyrrolpigmente, 19. Mitt.: Die elektrochemische Oxidation von Pyrromethenonen und Pyrromethenen (Gallenpigment-Partialstrukturen)

The electrochemical oxidation of arylmethylene-pyrrolinones, pyrromethenones and pyrromethenes as representative bile pigment partial structure models was investigated by means of a rotating disc platinum electrode using acetonitrile as the solvent. Two different oxidation reactions were found. The first reaction being a reversible one-electron oxidation with compounds of the arylmethylene-pyrrolinone series and pyrromethenones which are unsubstituted in position 5 of the pyrrole ring. A two step reaction (the first one reversible, the second irreversible) on the other hand was found to be typical for pyrromethenones bearing a methyl group in this position.Through protonation the first step is at a higher potential, whereas the second one is lowered and becomes reversible. The resulting oxidation pattern can be interpreted analogous to the oxidation of hydroquinones in aprotic solvents.The geometrical isomers of a pyrromethenone were oxidized at appr. the same potential, but there is a strong dependence of the potential of the first oxidation step on the substitution: a higher degree of alkylation favours oxidation by lowering the oxidation potential.

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Living Free Radical Polymerisation Under a Constant Source of Gamma Radiation – An Example of Reversible Addition‐Fragmentation Chain Transfer or Reversible Termination?

The primary mechanism for living polymerisation under a source of gamma radiation at low dose rates is shown to be reversible addition‐fragmentation chain transfer. This was demonstrated by showing that the initial transfer step determines the success of the polymerisation. When an inappropriate leaving group is chosen for the RAFT agent, the polymerisation is non‐living. Under a reversible termination mechanism the ‘living’‐ness should be independent of this initial transfer step.     

Z(basic)--a novel purification tag for efficient protein recovery

A positively charged protein domain, Z(basic), can be used as a general purification tag to achieve efficient recovery of recombinantly produced target proteins using cation-exchange chromatography. To construct a protein domain usable for ion-exchange chromatography, the surface of protein Z was engineered to be highly charged, which allowed for selective capture of target proteins on a cation-exchanger at physiological pH values. Interestingly, the novel domain, denoted Z(basic), was shown to be selective also under denaturing conditions and could preferably be used for purification of proteins solubilised from inclusion bodies. Moreover, a flexible process for solid-phase refolding was developed, using Z(basic) as a reversible linker to the cation-exchanger resin. This procedure has the inherited advantage of combining purification and refolding into a single step and still enabling elution of a concentrated product in a suitable buffer. This article summarizes development and use of the Z(basic) tag in small and pilot-plant-scale downstream processing.     

Shape-persistent macrocycles: structures and synthetic approaches from arylene and ethynylene building blocks

Shape-persistent arylene ethynylene macrocycles have attracted much attention in supramolecular chemistry and materials science because of their unique structures and novel properties. In this Review we describe recent examples of macrocycle synthesis by cross-coupling (Sonogashira: aryl acetylene macrocycle or Glaser: aryl diacetylene macrocycle) and dynamic covalent chemistry. The primary disadvantage of the coupling methods is the kinetically determined product distribution, since a significant portion of oligomers grow beyond the length of the cyclic targets ("overshooting"). Better results have been obtained recently by a dynamic covalent approach involving reversible metathesis reactions that afford macrocycles in one step. Mechanistic studies demonstrate that macrocycle formation is thermodynamically controlled by this route. Remaining synthetic challenges include the efficient preparation of site-specifically functionalized structures and larger, more complex two- and three-dimensional molecules.     

Kinetic analysis of reversible thermal decomposition of solids

The isoconversional method was used to elucidate the kinetics of reversible solid-state reactions occurring under nonisothermal linear heating. The characteristic dependencies of the effective activation energy (E) on the extent of conversion (W) were established for two model processes: a reversible first-order reaction and a reversible reaction followed by an irreversible one. For the first process, E is almost independent of W and varies between the activation energy of the direct and inverse reaction. For the second, process with an endothermic reversible step, the dependence of E on W is of decreasing shape. The effective activation energy is limited by the sum of the activation energy of the irreversible reaction and the enthalpy of the reversible reaction, at low conversions, and by the activation energy of the irreversible reaction at high conversions. Analyses of the kinetic data for the dehydration of crystalhydrates, as well as other processes proceeding through a reversible step, show the dependencies of E on W characteristic of a reversible reaction followed by an irreversible one. © 1995 John Wiley & Sons, Inc.