The SHAPES strategy: an NMR-based approach for lead generation in drug discovery
The SHAPES strategy: an NMR-based approach for lead generation in drug discovery
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DOI：
10.1016/s1074-5521(00)80022-8
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发表时间：
1999-10-01
影响因子：
--
通讯作者：
Moore, JM
中科院分区：
文献类型：
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作者：
Fejzo, J;Lepre, CA;Moore, JM
背景资料：最近，已经显示核磁共振（NMR）可以用于鉴定与低分子量蛋白质药物靶标结合的配体。认识到NMR作为一个非常敏感的方法检测结合的效用，我们一直专注于开发替代方法，适用于较大的分子量的药物靶点，并不需要同位素labeling.Results：一种新的方法铅代（形状）描述，使用NMR检测结合的一个有限的，但多样的小分子库的一个潜在的药物靶。化合物支架衍生自已知治疗剂中最常见的形状，使用微分线增宽或转移NOE实现低（μ M-mM）亲和力结合的NMR检测（核Overhauser效应）NMR技术。用于通过NMR产生先导化合物的SHAPES方法对于在药物设计程序的早期识别潜在的先导化合物类别是有用的，并且容易与其他发现工具如虚拟筛选、高通量筛选和组合化学集成。
Background: Recently, it has been shown that nuclear magnetic resonance (NMR) may be used to identify ligands that bind to low molecular weight protein drug targets. Recognizing the utility of NMR as a very sensitive method for detecting binding, we have focused on developing alternative approaches that are applicable to larger molecular weight drug targets and do not require isotopic labeling.Results: A new method for lead generation (SHAPES) is described that uses NMR to detect binding of a limited but diverse library of small molecules to a potential drug target. The compound scaffolds are derived from shapes most commonly found in known therapeutic agents, NMR detection of low (mu M-mM) affinity binding is achieved using either differential line broadening or transferred NOE (nuclear Overhauser effect) NMR techniques.Conclusions: The SHAPES method for lead generation by NMR is useful for identifying potential lead classes of drugs early in a drug design program, and is easily integrated with other discovery tools such as virtual screening, high-throughput screening and combinatorial chemistry.