Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery.
Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery.
复制标题
将药物化学扩展到3D空间：金属碎片作为基于碎片的药物发现的3D支架。
DOI：
10.1039/c9sc05586j
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发表时间：
2019-12-12
期刊：
影响因子：
8.4
通讯作者：
Cohen SM
中科院分区：
文献类型：
--
作者：
Morrison CN;Prosser KE;Stokes RW;Cordes A;Metzler-Nolte N;Cohen SM
基于片段的药物发现（FBDD）是鉴定新的生物活性分子的有力策略。FBDD依赖于片段文库，通常大小适中，但化学多样性高。虽然在FBDD文库中已经在许多方面实现了良好的化学多样性，但是实现形状多样性-特别是具有三维（3D）结构的片段-仍然具有挑战性。最近的一项分析表明，所有传统的有机碎片中，>75%的碎片主要是1D或2D形状。然而，3D片段是期望的，因为分子形状是生物分子识别分子的最重要因素之一。为了解决这一挑战，引入了使用惰性金属络合物（所谓的“金属碎片”（mFs））来构建3D片段库。一个适度的库71化合物已准备丰富的形状多样性，通过归一化的主惯性矩（PMI）分析。PMI分析表明，这些金属碎片占据的片段空间的区域是独特的和高度代表性不足时，与传统的有机片段库，是由数量级更多的分子。通过对几种不同类型的蛋白质进行筛选，包括抗病毒、抗菌和抗癌靶标，证明了该金属片段文库的潜在价值。通过测定选择片段对几种蛋白质的IC 50和热位移值，验证了金属片段对未来电极导线开发的适用性。这些发现证明了金属片段库作为针对各种蛋白质靶标的FBDD访问未充分利用的3D片段空间的手段的实用性。基于碎片的药物发现（FBDD）是利用三维金属碎片进行生物活性分子鉴定的一种新策略。
Fragment-based drug discovery (FBDD) is a powerful strategy for the identification of new bioactive molecules. FBDD relies on fragment libraries, generally of modest size, but of high chemical diversity. Although good chemical diversity in FBDD libraries has been achieved in many respects, achieving shape diversity – particularly fragments with three-dimensional (3D) structures – has remained challenging. A recent analysis revealed that >75% of all conventional, organic fragments are predominantly 1D or 2D in shape. However, 3D fragments are desired because molecular shape is one of the most important factors in molecular recognition by a biomolecule. To address this challenge, the use of inert metal complexes, so-called ‘metallofragments’ (mFs), to construct a 3D fragment library is introduced. A modest library of 71 compounds has been prepared with rich shape diversity as gauged by normalized principle moment of inertia (PMI) analysis. PMI analysis shows that these metallofragments occupy an area of fragment space that is unique and highly underrepresented when compared to conventional organic fragment libraries that are comprised of orders of magnitude more molecules. The potential value of this metallofragment library is demonstrated by screening against several different types of proteins, including an antiviral, an antibacterial, and an anticancer target. The suitability of the metallofragments for future hit-to-lead development was validated through the determination of IC50 and thermal shift values for select fragments against several proteins. These findings demonstrate the utility of metallofragment libraries as a means of accessing underutilized 3D fragment space for FBDD against a variety of protein targets. Fragment-based drug discovery (FBDD) using 3-dimensional metallofragments is a new strategy for the identification of bioactive molecules.
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影响因子：
3.8
作者：
Grzegorczyk, Marek;Kapturkiewicz, Andrzej;Trojanowska, Agnieszka
通讯作者：
Trojanowska, Agnieszka
有机金属抗癌化合物。
影响因子：
7.3
作者：
Gasser G;Ott I;Metzler-Nolte N
通讯作者：
Metzler-Nolte N
影响因子：
16.6
作者：
Can, Daniel;Spingler, Bernhard;Alberto, Roger
通讯作者：
Alberto, Roger
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.5
作者：
Heo, Young-A
通讯作者：
Heo, Young-A