NMR-based screening in drug discovery
NMR-based screening in drug discovery
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DOI：
10.1017/s0033583500003528
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发表时间：
1999-08-01
影响因子：
6.1
通讯作者：
Fesik, SW
中科院分区：
文献类型：
--
作者：
Hajduk, PJ;Meadows, RP;Fesik, SW
1.引言2112.筛选方法2132.1化学位移2132.2扩散2142.3横向弛豫2182.4核过度效应。药物发现和设计策略2213.1基于片段的方法2213.1.1链接片段方法2213.1.2直接组合文库2223.1.3高亲和力配体的修饰2233.1.4溶剂作图技术2233.2基于高通量核磁共振的筛选2243.3酶分析2264。发现新的配体2274.1 FKBP的高亲和力配体2274.2基质分解蛋白的有效抑制剂2294.3 E2蛋白的dna结合区域的配体2334.4发现ERm甲基转移酶抑制剂2334.5针对SH22365区域的磷酸酪氨酸模拟物。结论2376。参考文献237药物发现过程中的一个关键步骤是鉴定用于大分子靶标的高亲和力配体。传统上，这种先导化合物的鉴定是通过对公司化合物储存库的高通量筛选(HTS)完成的。传统的HTS方法在制药行业中得到了广泛的应用和成功，并通过最近在筛查方面的技术进步(Fernandes，1998；Oldenburg等人)。1998年；Silverman等人。1998)和组合化学(Fuchhere等人)。1998年；Fecik等人。1998年)，这些项目将继续在药物发现中发挥重要作用。然而，使用传统方法并不总是能找到合适的线索。这并不令人惊讶，因为与估计的1050-1080种化合物相比，典型的公司图书馆包含的化合物不到106种(Martin，1997)。此外，大多数传统的分析方法仅限于筛选针对已知功能的蛋白质的化合物文库，不包括从基因组学研究中获得的大量靶标。最近，一些基于核磁共振的筛选方法已被用于识别和设计蛋白质靶标的先导配体(见表1)。这些基于核磁共振的策略可以增强正在进行的常规HTS以识别线索，并可用于帮助线索优化。所有这些技术都利用了这样一个事实，即当目标分子和配体之间形成络合物时，目标或配体的核磁共振敏感参数可以观察到显著的扰动。这些扰动可以用来定性地检测配基结合或定量地评估结合作用的强度。此外，一些技术还允许识别配体结合位置或配体的哪一部分负责与靶标相互作用。本文综述了基于核磁共振的筛选技术的研究现状。
1. Introduction 2112. Screening methods 2132.1 Chemical shifts 2132.2 Diffusion 2142.3 Transverse relaxation 2182.4 Nuclear Overhauser effects 2183. Strategies for drug discovery and design 2213.1 Fragment-based methods 2213.1.1 Linked-fragment approach 2213.1.2 Directed combinatorial libraries 2223.1.3 Modification of high-affinity ligands 2233.1.4 Solvent mapping techniques 2233.2 High-throughput NMR-based screening 2243.3 Enzymatic assays 2264. Discovery of novel ligands 2274.1 High-affinity ligands for FKBP 2274.2 Potent inhibitors of stromelysin 2294.3 Ligands for the DNA-binding domain of the E2 protein 2334.4 Discovery of Erm methyltransferase inhibitors 2334.5 Phosphotyrosine mimetics for SH2 domains 2365. Conclusions 2376. References 237A critical step in the drug discovery process is the identification of high-affinity ligands for macromolecular targets. Traditionally, the identification of such lead compounds has been accomplished through the high-throughout screening (HTS) of corporate compound repositories. Conventional HTS methodology has enjoyed widespread application and success in the pharmaceutical industry and, through recent technological advances in screening (Fernandes, 1998; Oldenburg et al. 1998; Silverman et al. 1998) and combinatorial chemistry (Fauchere et al. 1998; Fecik et al. 1998), these programs will continue to have a prominent role in drug discovery. However, suitable leads cannot always be found using conventional methods. This is not surprising since typical corporate libraries contain fewer than 106 compounds compared with the estimated 1050–1080 universe of compounds (Martin, 1997). In addition, most conventional assays are limited to screening libraries of compounds against proteins with known function, excluding the large number of targets becoming available from genomics research.Recently, a number of NMR-based screening methods have been employed to identify and design lead ligands for protein targets (see Table 1). These NMR-based strategies can augment ongoing conventional HTS for identifying leads and can be used to aid in lead optimization. All of these techniques take advantage of the fact that upon complex formation between a target molecule and a ligand, significant perturbations can be observed in NMR-sensitive parameters of either the target or the ligand. These perturbations can be used qualitatively to detect ligand binding or quantitatively to assess the strength of the binding interaction. In addition, some of the techniques allow the identification of the ligand binding site or which part of the ligand is responsible for interacting with the target. In this article, the current state of NMR-based screening is reviewed.