苯甲酰苯并咪唑类选择性抑制剂靶向隐孢子虫和刚地弓形虫钙依赖蛋白激酶-1。
Benzoylbenzimidazole-based selective inhibitors targeting Cryptosporidium parvum and Toxoplasma gondii calcium-dependent protein kinase-1.
机构信息
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
出版信息
Bioorg Med Chem Lett. 2012 Aug 15;22(16):5264-7. doi: 10.1016/j.bmcl.2012.06.050. Epub 2012 Jun 23.
Abstract
Calcium-dependent protein kinase-1 (CDPK1) from Cryptosporidium parvum (CpCDPK1) and Toxoplasma gondii (TgCDPK1) have become attractive targets for discovering selective inhibitors to combat infections caused by these protozoa. We used structure-based design to improve a series of benzoylbenzimidazole-based compounds in terms of solubility, selectivity, and potency against CpCDPK1 and TgCDPK1. The best inhibitors show inhibitory potencies below 50 nM and selectivity well above 200-fold over two human kinases with small gatekeeper residues.
摘要
钙依赖蛋白激酶-1（CDPK1）来自隐孢子虫（CpCDPK1）和刚地弓形虫（TgCDPK1），已成为发现选择性抑制剂以对抗这些原生动物感染的有吸引力的靶标。我们使用基于结构的设计来提高一系列苯甲酰苯并咪唑类化合物的溶解度、选择性和对 CpCDPK1 和 TgCDPK1 的效力。最好的抑制剂显示出低于 50 nM 的抑制效力和对两种带有小门卫残基的人类激酶的选择性超过 200 倍。
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本文引用的文献
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