PDF(Pubmed)
Abstract：
The growing interest in Kv7.2/7.3 agonists originates from the involvement of these channels in several brain hyperexcitability disorders. In particular, Kv7.2/7.3 mutants have been clearly associated with epileptic encephalopathies (DEEs) as well as with a spectrum of focal epilepsy disorders, often associated with developmental plateauing or regression. Nevertheless, there is a lack of available therapeutic options, considering that retigabine, the only molecule used in clinic as a broad-spectrum Kv7 agonist, has been withdrawn from the market in late 2016. This is why several efforts have been made both by both academia and industry in the search for suitable chemotypes acting as Kv7.2/7.3 agonists. In this context, in silico methods have played a major role, since the precise structures of different Kv7 homotetramers have been only recently disclosed. In the present review, the computational methods used for the design of Kv.7.2/7.3 small molecule agonists and the underlying medicinal chemistry are discussed in the context of their biological and structure-function properties.
摘要：
对Kv7.2/7.3激动剂日益增长的兴趣源于这些通道参与几种大脑过度兴奋障碍。特别是,Kv7.2/7.3突变体与癫痫性脑病（DEE）以及一系列局灶性癫痫疾病明显相关。通常与发育平稳或退化有关。然而，缺乏可用的治疗选择，考虑到瑞替加宾，临床上唯一用作广谱Kv7激动剂的分子，已于2016年底退出市场。这就是为什么学术界和工业界在寻找充当Kv7.2/7.3激动剂的合适的化学型方面都做出了一些努力。在这种情况下，计算机方法发挥了重要作用，因为不同的Kv7同源四聚体的精确结构直到最近才被公开。在本次审查中，在其生物学和结构功能特性的背景下，讨论了用于设计Kv.7.2/7.3小分子激动剂的计算方法和潜在的药物化学。
