Department of Chemistry and Biochemistry, University of Texas, Austin, TX 78712, USA.
Toxins (Basel). 2011 Oct;3(10):1233-48. doi: 10.3390/toxins3101233. Epub 2011 Oct 13.
Ricin is a potent cytotoxin easily purified in large quantities. It presents a significant public health concern due to its potential use as a bioterrorism agent. For this reason, extensive efforts have been underway to develop antidotes against this deadly poison. The catalytic A subunit of the heterodimeric toxin has been biochemically and structurally well characterized, and is an attractive target for structure-based drug design. Aided by computer docking simulations, several ricin toxin A chain (RTA) inhibitors have been identified; the most promising leads belonging to the pterin family. Development of these lead compounds into potent drug candidates is a challenging prospect for numerous reasons, including poor solubility of pterins, the large and highly polar secondary binding pocket of RTA, as well as the enzyme's near perfect catalytic efficiency and tight binding affinity for its natural substrate, the eukaryotic ribosome. To date, the most potent RTA inhibitors developed using this approach are only modest inhibitors with apparent IC(50) values in the 10(-4) M range, leaving significant room for improvement. This review highlights the variety of techniques routinely employed in structure-based drug design projects, as well as the challenges faced in the design of RTA inhibitors.
蓖麻毒素是一种有效的细胞毒素，很容易大量纯化。由于其可能被用作生物恐怖主义制剂，因此对其产生了极大的公共卫生关注。出于这个原因，人们一直在努力开发针对这种致命毒药的解毒剂。该异二聚体毒素的催化 A 亚基已在生化和结构上得到了很好的表征，并且是基于结构的药物设计的有吸引力的靶标。借助计算机对接模拟，已经鉴定出几种蓖麻毒素 A 链（RTA）抑制剂；最有前途的先导化合物属于蝶呤家族。由于多种原因，将这些先导化合物开发成有效的候选药物具有挑战性，包括蝶呤的溶解度差、RTA 的大而高度极性的二级结合口袋、以及酶对其天然底物真核核糖体的近乎完美的催化效率和紧密结合亲和力。迄今为止，使用这种方法开发的最有效的 RTA 抑制剂只是适度抑制剂，其表观 IC（50）值在 10（-4）M 范围内，仍有很大的改进空间。本文综述了基于结构的药物设计项目中常用的各种技术，以及在设计 RTA 抑制剂时面临的挑战。
