Advances in the design of a multipurpose fragment screening library
Advances in the design of a multipurpose fragment screening library
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DOI：
10.1517/17460441.2013.780022
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发表时间：
2013-04
影响因子：
6.3
通讯作者：
F. Wilde;A. Link
中科院分区：
文献类型：
--
作者：
F. Wilde;A. Link
简介：基于片段的先导化合物发现（FBLD）已经从一种新兴技术发展成为药物研究中的最先进方法。片段文库用于发现命中和产生先导结构的有效使用已经在学术界和制药工业中越来越多地实现，但是适当片段的仔细或最佳选择仍然是一项艰巨的任务，特别是当片段旨在用于在多于一个或甚至多种和困难的靶标中产生先导时。涵盖的领域：在非商业筛选收集的片段状化合物存放在学术机构的多种筛选目的的进展进行审查，以及为产生苗条和匀称的新平台的多样性的方法。考虑了最近关于多用途片段筛选文库的文献和2012年8月在柏林举行的EFMC-ISMC会议上发表的论文。专家意见：现有的片段库往往侧重于富含sp 2的化合物，涵盖了化学空间的充分探索领域。为了提高命中的质量并能够解决看似无法治疗的目标，扁平支架应该被以sp3杂交为主的形状良好的分子核心所取代。需要结构新颖的片段，在这方面，卤键的作用被低估了。汇集策略的片段鸡尾酒必须被设计为检测同时结合的弱配体在附近：合作的结合是太重要了，依赖于偶然的发现。
Introduction: Fragment-based lead discovery (FBLD) has evolved from an emerging technology to a state-of-the-art approach in drug research. The efficacious use of fragment libraries for the discovery of hits and generation of lead structures has to an increasing extent become implemented both within academia and the pharmaceutical industry but the careful or optimal selection of appropriate fragments remains a demanding task, especially when fragments are intended for the lead generation in more than one or even diverse and difficult targets. Areas covered: Progress in non-commercial screening collections of fragment-like compounds for multiple screening purposes deposited at academic institutions is reviewed as well as approaches for the generation of slim and shapely novel platforms for diversity. Recent literature on multipurpose fragment screening libraries and the papers presented at the EFMC-ISMC meeting in Berlin in August 2012 have been taken into account. Expert opinion: Existing fragment libraries tend to focus on sp 2-rich compounds covering well-explored areas of chemical space. In order to improve the quality of the hits and to be able to tackle seemingly undruggable targets, flat scaffolds should be replaced by shapely molecular cores dominated by sp 3 hybridization. Structurally novel fragments are needed and in this respect, the role of halogen bonds has been underestimated. Pooling strategies for fragment cocktails must be designed to detect simultaneous binding of weak ligands in close proximity: cooperative binding is too important to rely on chance discoveries.