Preface [Hot Topic: Bead Technologies and Post-Genomic Drug Discovery (Guest Editor: Gerard Rosse)]

Gerard Rosse

摘要

Both the completion of the Human Genome Project and the sequencing of the genetic codes of microorganisms are providing the unique opportunity to understand Life better and consequently are producing a vast number of potential targets for therapeutic intervention. There is a great need for novel, intelligent strategies for identifying valid targets and discovering druglike leads against them. This Special Issue provides an overview of bead technologies in the everyday practice of drug research. Bead technologies are defined here as a broad term covering combinatorial chemistry approaches based on polymer beads (e.g. solidphase synthesis, polymer supported reagents, on bead assays, etc.).nnDrug discovery proceeds as a multi-stage process from the identification of a potential therapeutic target through lead generation, lead optimization to clinical testing before a drug product is marketed. The first series of reviews are focused on the application of bead technologies at the very early stage of drug discovery, namely genomics and proteomics. A single polymer bead can be considered as a miniaturized reactor which is carrying a chemical entity and in which a biological assay can be performed. The application of a multiplexed bead-based assay is described in the first review of this collection by Yingyongnarongkul, How, Diaz-Mochon, Muzerelle and Bradley. They provide a comprehensive review of the role of beadbased assays for high-throughput screening, gene expression, single nucleotide polymorphism and genomic analysis. The review of Groth, Renil and Meinjohanns focuses on techniques based on biocompatible polymers and combining both high throughput organic synthesis and high throughput screening in one process.nnIn the fields of chemical genetics and chemogenomics, chemical entities are exploited to identify and characterize proteins and to understand the cellular processes in which they operate. In groundbreaking work in this area, Eguchi, McMillan, Nguyen, Teo, Chi, Henderson and Kahn describe the concept of peptide secondary structural mimetics within chemogenomics. In a broader review of the subject, Thorpe summarizes the application of compound arrays generated from solid-phase chemistries to the field of forward and reverse chemical genetics.nnThe selection of a therapeutic target is followed by the identification and optimization of lead structures. The synthesis of combinatorial libraries is today well recognized as a successful approach to generate novel chemical entities for the identification of new leads. The next series of review articles demonstrate the importance of solid-phase organic synthesis to generate libraries. The review of Goodnow, Guba and Haap focuses on design approaches to deliver small molecule libraries that will increase the success of lead optimization. The concept of chemical biology applied to a target family is explored in the review of Park and Kimmich, in which chemical libraries directed for protein kinases are described. Natural products have been one of the major sources of leads and drugs. In their review Knepper, Gil and Braese discuss the synthesis of complex molecules derived from natural products using solid-phase synthesis or chemistries assisted by polymer-bound reagents (one other component of bead technologies). Pulici, Cervi, Martina and Quartieri provide comprehensive coverage of a relatively new area of organic chemistry - multicomponent and domino reactions performed on solid-phase. In another variation of solidphase organic synthesis, Michalek, Horn, Tzschucke and Bannwarth describe the use of catalysts non-covalently bound to the polymer. The mechanisms of organic reactions on a solid support are not well understood, and the difficulties of transferring chemistry from solution to solid phase have discouraged many chemists. The final review by Schroeder provides perspectives on the application of NMR methods to monitor reaction steps and describe the interpretation and validation of the structures of complex molecules while attached to polymer beads. I would like to acknowledge the scientists for their excellent contributions and the experts that helped review the manuscripts for this issue. This collection of reviews, mini-reviews and research articles was assembled to illustrate the critical significance of bead technologies along the value chain of the drug discovery process. Considering the many uses of such techniques, we can expect the development of exciting new approaches and applications in the coming years.

机译：人类基因组计划的完成以及微生物遗传密码的测序都提供了独特的机会，使人们可以更好地了解生命，因此产生了许多潜在的治疗干预目标。迫切需要新颖，智能的策略来识别有效靶标并发现针对它们的药物样铅。本期专刊概述了药物研究日常实践中的微珠技术。珠子技术在这里定义为广义术语，涵盖基于聚合物珠子的组合化学方法（例如，固相合成，聚合物支持的试剂，基于珠子的测定法等）。nn药物发现是从鉴定潜在治疗剂开始的多阶段过程通过销售线索来实现目标，在销售药品之前将线索优化到临床测试。第一组综述着重于药物发现早期的珠技术的应用，即基因组学和蛋白质组学。可以将单个聚合物珠粒视为携带化学实体并且可以在其中进行生物学测定的小型化反应器。 Yingyongnarongkul，How，Diaz-Mochon，Muzerelle和Bradley在对该收藏的第一篇评论中描述了基于多重磁珠的测定的应用。他们全面综述了基于珠的检测在高通量筛选，基因表达，单核苷酸多态性和基因组分析中的作用。 Groth，Renil和Meinjohanns的综述着重于基于生物相容性聚合物的技术，并将高通量有机合成和高通量筛选结合在一个过程中。在化学遗传学和化学基因组学领域，化学实体被用来鉴定和表征蛋白质并了解它们在其中运作的细胞过程。在这一领域的开创性工作中，Eguchi，McMillan，Nguyen，Teo，Chi，Henderson和Kahn描述了化学基因组学中肽二级结构模拟物的概念。在对该主题的更广泛综述中，索普总结了由固相化学产生的化合物阵列在正向和反向化学遗传学领域中的应用。选择治疗靶点之后，是对前导结构的鉴定和优化。如今，组合库的合成已被公认为是一种成功的方法，可以生成新的化学实体来识别新的潜在客户。接下来的系列评论文章证明了固相有机合成生成文库的重要性。对Goodnow，Guba和Haap的评论集中于提供小分子库的设计方法，这些方法将增加潜在客户优化的成功率。在Park和Kimmich的综述中探索了将化学生物学概念应用于目标家族的方法，其中描述了针对蛋白激酶的化学文库。天然产物一直是铅和药物的主要来源之一。在Knepper，Gil和Braese的评论中，他们讨论了利用固相合成或由聚合物结合的试剂（珠技术的另一组成部分）辅助的化学方法，合成天然产物衍生的复杂分子的方法。 Pulici，Cervi，Martina和Quartieri提供了相对较新的有机化学领域的全面报道-在固相上进行的多组分和多米诺反应。在固相有机合成的另一个变体中，Michalek，Horn，Tzschucke和Bannwarth描述了与聚合物非共价键合的催化剂的使用。固体载体上有机反应的机理尚未得到很好的理解，将化学从溶液转移到固相的困难使许多化学家望而却步。 Schroeder的最终评论提供了有关NMR方法在监测反应步骤中的应用的观点，并描述了附着在聚合物珠上的复杂分子结构的解释和验证。我要感谢科学家们的杰出贡献以及帮助审查此问题的手稿的专家。收集了这些评论，小型评论和研究文章，以说明珠子技术在药物发现过程价值链中的关键意义。考虑到此类技术的许多用途，我们可以期待在未来几年中将开发出令人兴奋的新方法和应用。

Preface [Hot Topic: Bead Technologies and Post-Genomic Drug Discovery (Guest Editor: Gerard Rosse)]

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