structure-based design of ricin inhibitors基于结构的蓖麻毒素抑制剂的设计.pdf

Toxins 2011, 3, 1233-1248; doi:10.3390/toxins3101233 OPEN ACCESS toxins ISSN 2072-6651 /journal/toxins Review Structure-Based Design of Ricin Inhibitors Karl Jasheway, Jeffrey Pruet, Eric V. Anslyn and Jon D. Robertus * Department of Chemistry and Biochemistry, University of Texas, Austin, TX 78712, USA; E-Mails: karl.jasheway@ (K.J.); jpruet@ (J.P.); anslyn@ (E.V.A.) * Author to whom correspondence should be addressed; E-Mail: jrobertus@; Tel.: +1-512-471-3175; Fax: +1-512-471-6135. Received: 11 August 2011; in revised form: 21 September 2011 / Accepted: 26 September 2011 / Published: 13 October 2011 Abstract: 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’