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Structure-Based Macrocycle Design in Small-Molecule Drug Discovery and Simple Metrics To Identify Opportunities for Macrocyclization of Small-Molecule Ligands.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-03-22 , DOI: 10.1021/acs.jmedchem.8b01985
Maxwell D Cummings 1 , Sivakumar Sekharan 2
Affiliation  

Interest is growing in the use of macrocycles in pharmaceutical discovery. Macrocylization may provide a gateway to an expanded chemical space for small-molecule drug discovery, and this could be beneficial in prosecuting difficult targets, e.g., protein-protein interactions. Most, but not all, macrocycle drugs are derived from natural products. Studies on synthetic drug-like small-molecule macrocycles are limited, and our current understanding of macrocycle drugs is similarly limited. Following some background discussion, we review several examples of the structure-based design of synthetic macrocycles. Our opinion is that in conformationally suitable systems macrocycles are an analog class worthy of consideration. We then summarize an approach for the initial evaluation of molecules as candidates for macrocyclization.

中文翻译:

小分子药物发现中的基于结构的大环设计和简单度量,以识别小分子配体大环化的机会。

在药物发现中使用大环化合物的兴趣正在增长。巨细胞化可以为小分子药物发现提供通往扩展的化学空间的途径,这对于起诉困难的靶标(例如蛋白质-蛋白质相互作用)可能是有益的。大多数但不是全部大环药物都来自天然产物。对合成类药物小分子大环化合物的研究是有限的,而我们目前对大环药物的了解也受到类似的限制。经过一些背景讨论,我们回顾了合成大环化合物基于结构的设计的几个例子。我们的观点是,在构象上合适的系统中,宏周期是一个值得考虑的模拟类。然后,我们总结了作为大环化候选对象的分子的初始评估方法。
更新日期:2019-03-12
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