The SGC beyond structural genomics: redefining the role of 3D structures by coupling genomic stratification with fragment-based discovery.
The SGC beyond structural genomics: redefining the role of 3D structures by coupling genomic stratification with fragment-based discovery.
复制标题
超越结构基因组学的 SGC：通过将基因组分层与基于片段的发现结合起来，重新定义 3D 结构的作用。
DOI：
10.1042/ebc20170051
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发表时间：
2017-11-08
影响因子：
6.4
通讯作者：
von Delft F
中科院分区：
文献类型：
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作者：
Bradley AR;Echalier A;Fairhead M;Strain-Damerell C;Brennan P;Bullock AN;Burgess-Brown NA;Carpenter EP;Gileadi O;Marsden BD;Lee WH;Yue W;Bountra C;von Delft F
基因组学数据的持续爆炸式增长早已超过了传统生化方法验证此类数据分析所产生的大量假设的能力。相比之下，尽管制备探针分子（或工具化合物）存在困难且成本高昂，但使用它们进行小分子药物发现的早期表型验证仍然是金标准。基于合理结构的配体发现方法长期以来一直有望提供缩小这种差距所需的效率；然而在实践中，由于诸多老生常谈的原因，尽管21世纪头十年的结构基因组学计划带来了巨大的技术进步，但这一期望在很大程度上仍未实现。因此，结构基因组学联盟（SGC）当前的第四个资助阶段，基于其在新型靶点的结构生物学和蛋白质抑制剂设计方面的丰富经验，试图重新定义为药物发现进行结构生物学研究的意义。我们提出了靶点赋能包（TEP）的概念，它通过试剂、检测方法和数据，提供了遗传疾病关联与开发有效化合物之间缺失的环节。这一目标包含多个方面：通过众包给合作专家网络严格评估靶点与遗传疾病的关联；建立一种系统的方法来生成构成每个靶点的TEP的方案和数据；开发新的基于X射线的片段技术，以便快速且低成本地生成高质量的化学物质；以及利用严格的开放获取模式在学术界和工业界建立多学科合作伙伴关系。通过学习如何扩展这些方法，SGC旨在使结构最终如最初预期的那样服务于基因组学，并展示3D结构如何系统地为整类靶点发现新的成药模式。
The ongoing explosion in genomics data has long since outpaced the capacity of conventional biochemical methodology to verify the large number of hypotheses that emerge from the analysis of such data. In contrast, it is still a gold-standard for early phenotypic validation towards small-molecule drug discovery to use probe molecules (or tool compounds), notwithstanding the difficulty and cost of generating them. Rational structure-based approaches to ligand discovery have long promised the efficiencies needed to close this divergence; in practice, however, this promise remains largely unfulfilled, for a host of well-rehearsed reasons and despite the huge technical advances spearheaded by the structural genomics initiatives of the noughties. Therefore the current, fourth funding phase of the Structural Genomics Consortium (SGC), building on its extensive experience in structural biology of novel targets and design of protein inhibitors, seeks to redefine what it means to do structural biology for drug discovery. We developed the concept of a Target Enabling Package (TEP) that provides, through reagents, assays and data, the missing link between genetic disease linkage and the development of usefully potent compounds. There are multiple prongs to the ambition: rigorously assessing targets’ genetic disease linkages through crowdsourcing to a network of collaborating experts; establishing a systematic approach to generate the protocols and data that comprise each target’s TEP; developing new, X-ray-based fragment technologies for generating high quality chemical matter quickly and cheaply; and exploiting a stringently open access model to build multidisciplinary partnerships throughout academia and industry. By learning how to scale these approaches, the SGC aims to make structures finally serve genomics, as originally intended, and demonstrate how 3D structures systematically allow new modes of druggability to be discovered for whole classes of targets.