Assessing the rigidity of cubanes and bicyclo(1.1.1)pentanes as benzene bioisosteres
Assessing the rigidity of cubanes and bicyclo(1.1.1)pentanes as benzene bioisosteres
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评估古巴烷和双环(1.1.1)戊烷作为苯生物等排体的刚性
DOI：
10.1016/j.bmc.2024.117652
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发表时间：
2024
影响因子：
3.5
通讯作者：
Pattison G
中科院分区：
文献类型：
--
作者：
Pattison G
芳香环是大多数药物化合物的关键核心亚结构。最近，人们对用苯的饱和生物电子等排体取代芳族结构产生了很大兴趣，所述苯的饱和生物电子等排体通常是稠环或桥环系统。与苯相比，这些生物电子等排体通常显示出改善的溶解度特性，并且还可以经历更少的不必要的代谢过程。芳香环在药物设计中如此成功的一个关键原因是它们的刚性。本文采用分子动力学模拟支持的晶体学数据来评估的刚性bicyclopentane和cubane环系统作为两个最常见的苯生物电子等排体，并比较这苯。虽然苯环在其二面角环灵活性方面比这两个生物电子等排体更灵活，但环周围的取代基在苯和生物电子等排体系中往往以更相似的方式表现。
Aromatic rings are critical core substructures in the majority of pharmaceutical compounds. There is much recent interest in replacing aromatic structures with saturated bioisosteres of benzene, which are generally fused or bridged ring systems. These bioisosteres often show improved solubility properties compared to benzene, and may also undergo fewer unwanted metabolic processes. One key reason why aromatic rings have proven so successful in drug design is their rigidity. This paper uses molecular dynamics simulations supported by crystallographic data to assess the rigidity of bicyclopentane and cubane ring systems as two of the most common benzene bioisosteres and compares this to benzene. Whilst a benzene ring is shown to be more flexible than these two bioisosteres in terms of its dihedral ring flexibility, substituents around the ring tend to behave in a much more similar way in both benzene and the bioisosteric systems.