糖精：一种用于碳酸酐酶IX抑制剂基于结构的药物设计的先导化合物。
Saccharin: a lead compound for structure-based drug design of carbonic anhydrase IX inhibitors.
作者信息
Mahon Brian P, Hendon Alex M, Driscoll Jenna M, Rankin Gregory M, Poulsen Sally-Ann, Supuran Claudiu T, McKenna Robert
机构信息
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA.
Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia.
出版信息
Bioorg Med Chem. 2015 Feb 15;23(4):849-54. doi: 10.1016/j.bmc.2014.12.030. Epub 2014 Dec 23.
Abstract
Carbonic anhydrase IX (CA IX) is a key modulator of aggressive tumor behavior and a prognostic marker and target for several cancers. Saccharin (SAC) based compounds may provide an avenue to overcome CA isoform specificity, as they display both nanomolar affinity and preferential binding, for CA IX compared to CA II (>50-fold for SAC and >1000-fold when SAC is conjugated to a carbohydrate moiety). The X-ray crystal structures of SAC and a SAC-carbohydrate conjugate bound to a CA IX-mimic are presented and compared to CA II. The structures provide substantial new insight into the mechanism of SAC selective CA isoform inhibition.
摘要
碳酸酐酶IX（CA IX）是侵袭性肿瘤行为的关键调节因子，也是多种癌症的预后标志物和靶点。基于糖精（SAC）的化合物可能提供一条克服CA同工型特异性的途径，因为它们对CA IX显示出纳摩尔亲和力和优先结合，与CA II相比（SAC为>50倍，SAC与碳水化合物部分缀合时为>1000倍）。本文展示了与CA IX模拟物结合的SAC和SAC-碳水化合物缀合物的X射线晶体结构，并与CA II进行了比较。这些结构为SAC选择性抑制CA同工型的机制提供了重要的新见解。
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